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1
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Wei J, Zhang X, Sui B, Ding X, Li Y, Liu B, Wang J, Lv X, Zhang Y, Jiang X, Yang Y, Lai H, Liu X, Shi J. Potassium-Doped MnO 2 Nanoparticles Reprogram Neutrophil Calcium Signaling to Accelerate Healing of Methicillin-Resistant Staphylococcus aureus-Infected Diabetic Wounds. ACS NANO 2025; 19:11807-11822. [PMID: 40100101 PMCID: PMC11966767 DOI: 10.1021/acsnano.4c14057] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 10/06/2024] [Revised: 03/08/2025] [Accepted: 03/10/2025] [Indexed: 03/20/2025]
Abstract
Neutrophils, as first-line immune cells, typically lose their edge within the diabetic wounds accompanied by methicillin-resistant Staphylococcus aureus (MRSA) infections (the D/M setting), playing the role of "more foe than friend" during the healing process. Specifically, reduced influx of calcium ions (Ca2+) and impaired calcium homeostasis yield the dysfunction of neutrophil sequential behaviors in pathogen killing and wound healing, manifesting as suppressed chemotaxis, decreased intracellular reactive oxygen species (ROS) generation, prolonged apoptosis, and retention of neutrophil extracellular traps (NETs). To address this challenge, this study fabricated potassium (K)-doped manganese dioxide nanoparticles (MnO2 NPs), which activated transmembrane Ca2+ channels by inducing neutrophil depolarization via electron transfer. Subsequently, this contributed to the initial Ca2+ influx and reprogrammed Ca2+-dependent behaviors of impaired neutrophils. Also, the potential antimicrobial capacity of K-MnO2 NPs created a favorable extracellular environment that restored calcium homeostasis, enabling apoptotic neutrophils to be removed timely. Therefore, the wounds treated with K-MnO2 NPs in the D/M setting exhibited potent resistance to MRSA and rapid healing, which could be attributed to the synergistic effects of K-MnO2 NPs in leveraging Ca2+ influx and maintaining calcium homeostasis. In brief, K-MnO2 NPs constitute an effective strategy to resist MRSA and rapid wound healing in the D/M setting.
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Affiliation(s)
- Jianxu Wei
- Department
of Oral and Maxillofacial Implantology, Shanghai Ninth People’s Hospital, Shanghai Jiao Tong University
School of Medicine; College of Stomatology, Shanghai Jiao Tong University;
National Center for Stomatology; National Clinical Research Center
for Oral Diseases; Shanghai Key Laboratory of Stomatology; Shanghai
Research Institute of Stomatology, Shanghai 200011, China
| | - Xiaomeng Zhang
- Department
of Oral and Maxillofacial Implantology, Shanghai Ninth People’s Hospital, Shanghai Jiao Tong University
School of Medicine; College of Stomatology, Shanghai Jiao Tong University;
National Center for Stomatology; National Clinical Research Center
for Oral Diseases; Shanghai Key Laboratory of Stomatology; Shanghai
Research Institute of Stomatology, Shanghai 200011, China
| | - Baiyan Sui
- Department
of Dental Materials, Shanghai Biomaterials Research & Testing
Center, Shanghai Ninth People’s Hospital,
Shanghai Jiao Tong University School of Medicine; College of Stomatology,
Shanghai Jiao Tong University; National Center for Stomatology; National
Clinical Research Center for Oral Diseases; Shanghai Key Laboratory
of Stomatology, Shanghai 200011, China
| | - Xinxin Ding
- Department
of Oral and Maxillofacial Implantology, Shanghai Ninth People’s Hospital, Shanghai Jiao Tong University
School of Medicine; College of Stomatology, Shanghai Jiao Tong University;
National Center for Stomatology; National Clinical Research Center
for Oral Diseases; Shanghai Key Laboratory of Stomatology; Shanghai
Research Institute of Stomatology, Shanghai 200011, China
| | - Yuan Li
- Department
of Oral and Maxillofacial Implantology, Shanghai Ninth People’s Hospital, Shanghai Jiao Tong University
School of Medicine; College of Stomatology, Shanghai Jiao Tong University;
National Center for Stomatology; National Clinical Research Center
for Oral Diseases; Shanghai Key Laboratory of Stomatology; Shanghai
Research Institute of Stomatology, Shanghai 200011, China
| | - Beilei Liu
- Department
of Oral and Maxillofacial Implantology, Shanghai Ninth People’s Hospital, Shanghai Jiao Tong University
School of Medicine; College of Stomatology, Shanghai Jiao Tong University;
National Center for Stomatology; National Clinical Research Center
for Oral Diseases; Shanghai Key Laboratory of Stomatology; Shanghai
Research Institute of Stomatology, Shanghai 200011, China
| | - Jiale Wang
- College
of Physics, Donghua University, Shanghai 201620, China
- Shanghai
Institute of Intelligent Electronics and Systems, Donghua University, Shanghai 201620, China
| | - Xiaolei Lv
- Department
of Oral and Maxillofacial Implantology, Shanghai Ninth People’s Hospital, Shanghai Jiao Tong University
School of Medicine; College of Stomatology, Shanghai Jiao Tong University;
National Center for Stomatology; National Clinical Research Center
for Oral Diseases; Shanghai Key Laboratory of Stomatology; Shanghai
Research Institute of Stomatology, Shanghai 200011, China
| | - Yi Zhang
- Department
of Oral and Maxillofacial Implantology, Shanghai Ninth People’s Hospital, Shanghai Jiao Tong University
School of Medicine; College of Stomatology, Shanghai Jiao Tong University;
National Center for Stomatology; National Clinical Research Center
for Oral Diseases; Shanghai Key Laboratory of Stomatology; Shanghai
Research Institute of Stomatology, Shanghai 200011, China
| | - Xue Jiang
- Department
of Oral and Maxillofacial Implantology, Shanghai Ninth People’s Hospital, Shanghai Jiao Tong University
School of Medicine; College of Stomatology, Shanghai Jiao Tong University;
National Center for Stomatology; National Clinical Research Center
for Oral Diseases; Shanghai Key Laboratory of Stomatology; Shanghai
Research Institute of Stomatology, Shanghai 200011, China
| | - Yijie Yang
- Department
of Oral and Maxillofacial Implantology, Shanghai Ninth People’s Hospital, Shanghai Jiao Tong University
School of Medicine; College of Stomatology, Shanghai Jiao Tong University;
National Center for Stomatology; National Clinical Research Center
for Oral Diseases; Shanghai Key Laboratory of Stomatology; Shanghai
Research Institute of Stomatology, Shanghai 200011, China
| | - Hongchang Lai
- Department
of Oral and Maxillofacial Implantology, Shanghai Ninth People’s Hospital, Shanghai Jiao Tong University
School of Medicine; College of Stomatology, Shanghai Jiao Tong University;
National Center for Stomatology; National Clinical Research Center
for Oral Diseases; Shanghai Key Laboratory of Stomatology; Shanghai
Research Institute of Stomatology, Shanghai 200011, China
| | - Xin Liu
- Department
of Dental Materials, Shanghai Biomaterials Research & Testing
Center, Shanghai Ninth People’s Hospital,
Shanghai Jiao Tong University School of Medicine; College of Stomatology,
Shanghai Jiao Tong University; National Center for Stomatology; National
Clinical Research Center for Oral Diseases; Shanghai Key Laboratory
of Stomatology, Shanghai 200011, China
| | - Junyu Shi
- Department
of Oral and Maxillofacial Implantology, Shanghai Ninth People’s Hospital, Shanghai Jiao Tong University
School of Medicine; College of Stomatology, Shanghai Jiao Tong University;
National Center for Stomatology; National Clinical Research Center
for Oral Diseases; Shanghai Key Laboratory of Stomatology; Shanghai
Research Institute of Stomatology, Shanghai 200011, China
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Banerjee D, Paul S, Selvan C, Pai S, Nandakumar BS, Mukherjee S, Raghavendra PB. Uncovering the Role of Tertiary Lymphoid Organs in the Inflammatory Landscape: A Novel Immunophenotype of Diabetic Foot Ulcers. J Cell Mol Med 2025; 29:e70479. [PMID: 40159626 PMCID: PMC11955414 DOI: 10.1111/jcmm.70479] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/18/2024] [Revised: 02/23/2025] [Accepted: 02/27/2025] [Indexed: 04/02/2025] Open
Abstract
Diabetes foot ulcers (DFU) are the most common foot injuries leading to lower extremity amputation. Our study aimed to provide the first representative analysis highlighting the vital role of Tertiary Lymphoid Organs (TLO) inflammatory landscape in diabetic foot ulcers. The study explores mechanisms of TLO formation and the disease-specific roles of TLOs in regulating peripheral inflammatory and immune responses. Additionally, comprehensive analysis of clinical data from DFU cases, focused on TLO pathophysiology and systemic immune-inflammation landscape, is documented, aiming to identify the risk factors contributing to the development of DFUs. Our experimental results showed very significant differences were observed among the IL-17 and IFN-γ cytokine levels between the DFU vs. Control and DFU vs. NIDFU (Non-Infectious Diabetic Foot Ulcers) groups, while minimal differences were observed in IL-6 and TNF-α cytokine levels. Immunohistochemistry staining or Immunophenotyping of DFU patient-derived wound samples for TLO inflammatory stratification showed remarkable differences between DFU, NIDFU, and control groups both in CD3+ T Cells and CD20+ B cells. Overall, our study findings highlight the perspective role of TLO in DFU mechanisms and its prudent role in regulating peripheral inflammatory-immune responses. TLO study-related significant findings might be one of the important mechanisms, and its effective unveil might be a valuable treatment modality for DFU-complications.
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Affiliation(s)
- Deboshmita Banerjee
- National Institute of Biomedical GenomicsKalyaniWest BengalIndia
- Regional Centre for Biotechnology (RCB)FaridabadHaryanaIndia
| | - Shouvik Paul
- National Institute of Biomedical GenomicsKalyaniWest BengalIndia
- Regional Centre for Biotechnology (RCB)FaridabadHaryanaIndia
| | - Chitra Selvan
- Department of Endocrinology and General SurgeryM. S. Ramaiah Medical College and HospitalsBengaluruIndia
| | - Sreekar Pai
- Department of Endocrinology and General SurgeryM. S. Ramaiah Medical College and HospitalsBengaluruIndia
| | - B. S. Nandakumar
- Department of Community MedicineM. S. Ramaiah Medical College and HospitalsBengaluruIndia
| | - Souvik Mukherjee
- National Institute of Biomedical GenomicsKalyaniWest BengalIndia
- Regional Centre for Biotechnology (RCB)FaridabadHaryanaIndia
| | - Pongali B. Raghavendra
- National Institute of Biomedical GenomicsKalyaniWest BengalIndia
- Regional Centre for Biotechnology (RCB)FaridabadHaryanaIndia
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Santamaria MP, Mathias-Santamaria IF, Ferreira Bonafé AC, Gonzalez OA, Kirakodu S, Monteiro MDF, Casarin RCV, Shaddox LM, Miguel MMV. Microbiome and Inflammatory Biomarkers Associated With Palatal Wound Healing. J Periodontal Res 2025. [PMID: 39801488 DOI: 10.1111/jre.13373] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/13/2024] [Revised: 11/20/2024] [Accepted: 11/21/2024] [Indexed: 01/18/2025]
Abstract
AIM The clinical outcomes of a variety of surgical procedures highly depend on tissue repair and show high variability among patients. There is a gap in the literature on how the host inflammatory response, the microbiome, and the interplay between them can influence oral mucosa healing. In this pilot study, we aimed to evaluate the microbiome and biomarkers profiles in patients who had desired versus undesired wound healing in the palatal mucosa. METHODS Seventeen patients underwent a free gingival graft (FGG) for socket preservation. Palatal wound closure (WC) and epithelization (EPT) were assessed clinically. Biofilm from the palatal wound was collected before the surgical procedure and 3, 7, 14, and 30 days postoperatively. The inflammatory exudate was sampled on Days 3 and 7. At 14 days posttreatment, patients were classified into two groups based on EPT rates: (1) undesired healing (UH) and (2) desired healing (DH). RESULTS No difference was observed in alfa diversity over time or between groups. In beta diversity, both UH and DH showed microbiome changes on Days 3-7 and 7, respectively, compared with the baseline (p = 0.01), returning to its initial condition 30 days later. There was a trend toward a different microbiome profile between groups on Day 7 (p = 0.08). Bacterium composition in DH showed a balance between healthy species and oral pathogens over time, whereas UH composition was characterized by microorganisms correlated with epithelium invasion/cytotoxicity; virulence factor upregulation; and oral diseases, such as periodontitis and aphthous stomatitis, until Day 30. UH showed an increase in IL-6, MCP-1, and MIP-1α over time, and DH showed a decrease in TIMP-1, IL-1β, and MIP-1α. On Days 3 and 7, MIP-1α and MMP-2 showed greater concentrations of DH in the intergroup assessment, and MCP-1 increased on Day 7 in UH. CONCLUSION Specific microbiome/inflammatory profiles are associated with DH and UH. TRIAL REGISTRATION NCT05171400.
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Affiliation(s)
- Mauro Pedrine Santamaria
- College of Dentistry, University of Kentucky, Lexington, Kentucky, USA
- Division of Periodontics, Institute of Science and Technology, São José dos Campos, São Paulo State University (UNESP), São Paulo, Brazil
| | | | - Ana Carolina Ferreira Bonafé
- Division of Periodontics, Institute of Science and Technology, São José dos Campos, São Paulo State University (UNESP), São Paulo, Brazil
| | | | | | | | | | | | - Manuela Maria Viana Miguel
- College of Dentistry, University of Kentucky, Lexington, Kentucky, USA
- Division of Periodontics, Institute of Science and Technology, São José dos Campos, São Paulo State University (UNESP), São Paulo, Brazil
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Islam MR, Mondol SM, Hossen MA, Khatun MP, Selim S, Amiruzzaman, Gomes DJ, Rahaman MM. First report on comprehensive genomic analysis of a multidrug-resistant Enterobacter asburiae isolated from diabetic foot infection from Bangladesh. Sci Rep 2025; 15:424. [PMID: 39748007 PMCID: PMC11696989 DOI: 10.1038/s41598-024-84870-7] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/25/2024] [Accepted: 12/27/2024] [Indexed: 01/04/2025] Open
Abstract
Enterobacter asburiae (E. asburiae) is a gram-negative rod-shaped bacterium which has emerging significance as an opportunistic pathogen having high virulence pattern and drug resistant properties. In this study, we present the detailed analysis of the whole genome sequence of a multidrug-resistant (MDR) E. asburiae strain BDW1M3 from Bangladesh. The isolate was collected from an infected foot wound of a diabetic foot ulcer patient. Through sophisticated genomic techniques encompassing whole genome sequencing and in-depth bioinformatic analyses, this research unveils a profound understanding of the isolate's antimicrobial resistance patterns, virulence determinants, biosynthetic gene clusters, metabolic pathways and pathogenic potential. The isolate displayed resistance to Ampicillin, Fosfomycin, Cefoxitin, Tigecycline, Meropenem, Linezolid, Vancomycin antibiotics and demonstrated the capacity for biofilm formation. Several antimicrobial resistance genes such as blaACT-2,fosA2, baeR, qnrE2, vanA and numbers of virulence genes including ybaJ, csrA, barA, uvrY, pgaD, hlyD, hlyC, terC, purD were detected. Metal resistance genes investigation revealed the presence of cusCFBA operon system, and many other genes including zntA, zitB, czrB. Prophage region of Myoviridae was detected. Comparative genomics with 47 whole genome sequence (n = 47) shed light on the genetic diversity of E. asburiae strains from diverse sources and countries, with a notable observation that strains from both human and non-human origins exhibited significant pathogenicity potential, genomic and phylogenomic relations hinting at potential cross-species transmission. Pangenome analysis indicated toward an expanding pangenome of E. asburiae. Further research and in-depth comprehensive studies are required to investigate the prevalence of E. asburiae in Bangladesh and emphasize towards unraveling the bacterium's inherent pathogenic potential and the intricate molecular mechanisms that underlie its resistance traits and virulence properties.
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Affiliation(s)
- Md Rafiul Islam
- Department of Microbiology, University of Dhaka, Dhaka, 1000, Bangladesh
| | | | - Md Azad Hossen
- Department of Microbiology, University of Dhaka, Dhaka, 1000, Bangladesh
| | - Mst Poli Khatun
- Department of Microbiology, University of Dhaka, Dhaka, 1000, Bangladesh
| | - Shahjada Selim
- Department of Endocrinology, Bangabandhu Sheikh Mujib Medical University, Dhaka, 1000, Bangladesh
| | - Amiruzzaman
- Department of Medicine, Sir Salimullah Medical College, Dhaka, 1000, Bangladesh
| | - Donald James Gomes
- Department of Microbiology, University of Dhaka, Dhaka, 1000, Bangladesh
| | - Md Mizanur Rahaman
- Department of Microbiology, University of Dhaka, Dhaka, 1000, Bangladesh.
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5
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Wang K, Zhao H, Zhao X, Zhang X, Zhang W, Cheng Y, Ge J. Photobiomodulation for diabetes and its complications: a review of general presentation, mechanisms and efficacy. Ann Med 2024; 56:2433684. [PMID: 39607829 PMCID: PMC11610354 DOI: 10.1080/07853890.2024.2433684] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/08/2024] [Revised: 06/12/2024] [Accepted: 08/01/2024] [Indexed: 11/30/2024] Open
Abstract
Diabetes mellitus is a metabolic disease that is marked by persistent hyperglycemia due to inadequate insulin secretion or insulin resistance. Its prevalence is increasing yearly. Diabetes mellitus can lead to serious health complications that are the primary cause of mortality and disability among diabetic patients, including diabetic retinopathy, diabetic foot ulcers, diabetic peripheral neuropathy, and diabetic periodontitis, and so on. Traditional treatments for diabetes and its complications still suffer from limited clinical efficacy and high therapeutic side effects. Photobiomodulation (PBM), which utilizes low levels of red or near-infrared laser to irradiate cells and tissues, has been shown to be efficacious for a wide range of organ damage. In this study, we focus on the application of PBM in diabetes and its complications and mechanisms, as well as the advantages, disadvantages with the aim of developing new ideas for the application of PBM.
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Affiliation(s)
- Keyan Wang
- Department of Ophthalmology, The Second Hospital of Jilin University, Changchun, China
- Department of Physiology, College of Basic Medical Sciences, Jilin University, Changchun, China
- China Japan Union Hospital of Jilin University, Changchun, China
| | - Hongwei Zhao
- Department of Physiology, College of Basic Medical Sciences, Jilin University, Changchun, China
| | - Xiaoqing Zhao
- China Japan Union Hospital of Jilin University, Changchun, China
| | - Xiaoyu Zhang
- China Japan Union Hospital of Jilin University, Changchun, China
| | - Wei Zhang
- Department of Physiology, College of Basic Medical Sciences, Jilin University, Changchun, China
| | - Yan Cheng
- Department of Ophthalmology, The Second Hospital of Jilin University, Changchun, China
| | - Jingyan Ge
- Department of Physiology, College of Basic Medical Sciences, Jilin University, Changchun, China
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Vargas Guerrero MG, Vonken L, Peters E, Lucchesi J, Arts JJC. Material Technologies for Improved Diabetic Foot Ulcer (DFU) Treatment: A Questionnaire Study of Healthcare Professionals' Needs. Biomedicines 2024; 12:2483. [PMID: 39595050 PMCID: PMC11592356 DOI: 10.3390/biomedicines12112483] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/24/2024] [Revised: 10/17/2024] [Accepted: 10/25/2024] [Indexed: 11/28/2024] Open
Abstract
Background/Objectives: Diabetic foot ulcers (DFUs) are a common and severe complication of diabetic patients, with significant global prevalence and associated health burdens, including high recurrence rates, lower-limb amputations, and substantial associated economic costs. This study aimed to understand the user needs of healthcare professionals treating diabetic foot ulcers for newly developed material technologies. Methods: An open-ended questionnaire was used to identify user needs, identify the limitations of current treatments, and determine the specific requirements for ideal treatment. This information was used to develop a list of key considerations for creating innovative material technologies to improve diabetic wound treatment results. Results: Most respondents indicated that they followed published treatment guidelines for DFUs but noted that treatment often required a case-specific approach. Antibiotics and surgical debridement were commonly used for infection control. The participants showed a strong preference for wound dressings with lasting antibacterial properties. Respondents identified ideal properties for new products, including ease of use, enhanced antibacterial properties, affordability, and targeted biological activity. The respondents also highlighted the importance of a holistic approach to DFU management, integrating product development with comprehensive care strategies and patient education. Conclusions: This study highlights the complexity of DFU care, emphasizing that no single product can address all treatment needs. Future materials could focus on combination therapies and specific use cases. Additionally, understanding global variations in treatment practices and educating users on the proper application of newly developed material technologies is crucial for improving the management of DFUs and patient outcomes.
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Affiliation(s)
- Marian Gabriela Vargas Guerrero
- Department of Orthopaedic Surgery, Maastricht University Medical Centre (MUMC+), 6229 HX Maastricht, The Netherlands; (M.G.V.G.)
- Laboratory for Experimental Orthopaedics, Faculty of Health, Medicine & Life Sciences, Maastricht University, 6229 ER Maastricht, The Netherlands
| | - Lieve Vonken
- Department of Health Promotion, Faculty of Health, Medicine & Life Sciences, Maastricht University, 6229 HA Maastricht, The Netherlands
| | - Erwin Peters
- Department of Orthopaedic Surgery, Maastricht University Medical Centre (MUMC+), 6229 HX Maastricht, The Netherlands; (M.G.V.G.)
| | | | - Jacobus J. C. Arts
- Department of Orthopaedic Surgery, Maastricht University Medical Centre (MUMC+), 6229 HX Maastricht, The Netherlands; (M.G.V.G.)
- Laboratory for Experimental Orthopaedics, Faculty of Health, Medicine & Life Sciences, Maastricht University, 6229 ER Maastricht, The Netherlands
- Department of Orthopaedic Biomechanics, Faculty of Biomedical Engineering, Eindhoven University of Technology, 5600 MB Eindhoven, The Netherlands
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7
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Durand BARN, Daher R, Grenga L, Morsli M, Armengaud J, Lavigne JP, Dunyach-Remy C. Interactions between Helcococcus kunzii and Staphylococcus aureus: How a commensal bacterium modulates the virulence and metabolism of a pathogen in a chronic wound in vitro model. BMC Microbiol 2024; 24:406. [PMID: 39394082 PMCID: PMC11468182 DOI: 10.1186/s12866-024-03520-0] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/17/2024] [Accepted: 09/13/2024] [Indexed: 10/13/2024] Open
Abstract
BACKGROUND Staphylococcus aureus is the predominant pathogen isolated in diabetic foot infections. Recently, the skin commensal bacterium, Helcococcus kunzii, was found to modulate the virulence of this pathogen in an in vivo model. This study aims to elucidate the molecular mechanisms underlying the interaction between these two bacterial species, using a proteomic approach. RESULTS Our results reveal that H. kunzii can coexist and proliferate alongside S. aureus in a Chronic Wound Media (CWM), thereby mimicking an in vitro chronic wound environment. We noted that the secreted proteome of H. kunzii induced a transcriptional effect on S. aureus virulence, resulting in a decrease in the expression level of agrA, a gene involved in quorum sensing. The observed effect could be ascribed to specific proteins secreted by H. kunzii including polysaccharide deacetylase, peptidoglycan DD-metalloendopeptidase, glyceraldehyde-3-phosphate dehydrogenase, trypsin-like peptidase, and an extracellular solute-binding protein. These proteins potentially interact with the agr system, influencing S. aureus virulence. Additionally, the virulence of S. aureus was notably affected by modifications in iron-related pathways and components of cell wall architecture in the presence of H. kunzii. Furthermore, the overall metabolism of S. aureus was reduced when cocultured with H. kunzii. CONCLUSION Future research will focus on elucidating the role of these excreted factors in modulating virulence.
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Affiliation(s)
- Benjamin A R N Durand
- Department of Microbiology and Hospital Hygiene, CHU Nîmes, VBIC, INSERM U1047, Univ Montpellier, Nîmes, France
| | - Riham Daher
- Department of Microbiology and Hospital Hygiene, CHU Nîmes, VBIC, INSERM U1047, Univ Montpellier, Nîmes, France
| | - Lucia Grenga
- Département Médicaments et Technologies pour la Santé (DMTS), Université Paris-Saclay, CEA, INRAE, Bagnols-sur-Cèze, SPI, France
| | - Madjid Morsli
- Department of Microbiology and Hospital Hygiene, CHU Nîmes, VBIC, INSERM U1047, Univ Montpellier, Nîmes, France
| | - Jean Armengaud
- Département Médicaments et Technologies pour la Santé (DMTS), Université Paris-Saclay, CEA, INRAE, Bagnols-sur-Cèze, SPI, France
| | - Jean-Philippe Lavigne
- Department of Microbiology and Hospital Hygiene, CHU Nîmes, VBIC, INSERM U1047, Univ Montpellier, Nîmes, France
| | - Catherine Dunyach-Remy
- Department of Microbiology and Hospital Hygiene, CHU Nîmes, VBIC, INSERM U1047, Univ Montpellier, Nîmes, France.
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8
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O'Connor MJ, Bartler AV, Ho KC, Zhang K, Casas Fuentes RJ, Melnick BA, Huffman KN, Hong SJ, Galiano RD. Understanding Staphylococcus aureus in hyperglycaemia: A review of virulence factor and metabolic adaptations. Wound Repair Regen 2024; 32:661-670. [PMID: 38853489 DOI: 10.1111/wrr.13192] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/05/2024] [Revised: 04/03/2024] [Accepted: 05/10/2024] [Indexed: 06/11/2024]
Abstract
Staphylococcus aureus is one of the most commonly detected bacteria in diabetic skin and soft tissue infections. The incidence and severity of skin and soft tissue infections are higher in patients with diabetes, indicating a potentiating mechanism of hyperglycaemia and infection. The goal of this review is to explore the metabolic and virulence factor adaptations of S. aureus under hyperglycaemic conditions. Primary data from identified studies were included and summarised in this paper. Understanding the nexus of hyperglycaemia, metabolism, and virulence factors provides insights into the complexity of diabetic skin and soft tissue infections attributed to S. aureus.
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Affiliation(s)
- Madeline J O'Connor
- Division of Plastic and Reconstructive Surgery, Northwestern University Feinberg School of Medicine, Chicago, Illinois, USA
- Creighton University School of Medicine, Phoenix, Arizona, USA
| | - Angelica V Bartler
- Division of Plastic and Reconstructive Surgery, Northwestern University Feinberg School of Medicine, Chicago, Illinois, USA
| | - Kelly C Ho
- Division of Plastic and Reconstructive Surgery, Northwestern University Feinberg School of Medicine, Chicago, Illinois, USA
| | - Kenneth Zhang
- Division of Plastic and Reconstructive Surgery, Northwestern University Feinberg School of Medicine, Chicago, Illinois, USA
| | - Rolando J Casas Fuentes
- Division of Plastic and Reconstructive Surgery, Northwestern University Feinberg School of Medicine, Chicago, Illinois, USA
| | - Bradley A Melnick
- Division of Plastic and Reconstructive Surgery, Northwestern University Feinberg School of Medicine, Chicago, Illinois, USA
- West Virginia School of Osteopathic Medicine, Lewisburg, West Virginia, USA
| | - Kristin N Huffman
- Division of Plastic and Reconstructive Surgery, Northwestern University Feinberg School of Medicine, Chicago, Illinois, USA
| | - Seok Jong Hong
- Division of Plastic and Reconstructive Surgery, Northwestern University Feinberg School of Medicine, Chicago, Illinois, USA
| | - Robert D Galiano
- Division of Plastic and Reconstructive Surgery, Northwestern University Feinberg School of Medicine, Chicago, Illinois, USA
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9
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Bakeer W, Gaafar M, El-Gendy AO, El Badry MA, Khalil MG, Mansour AT, Alharbi NK, Selim HMRM, Bendary MM. Proven anti-virulence therapies in combating methicillin- and vancomycin-resistant Staphylococcus aureus infections. Front Cell Infect Microbiol 2024; 14:1403219. [PMID: 39253327 PMCID: PMC11381379 DOI: 10.3389/fcimb.2024.1403219] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/19/2024] [Accepted: 07/04/2024] [Indexed: 09/11/2024] Open
Abstract
Introduction Despite years of efforts to develop new antibiotics for eradicating multidrug-resistant (MDR) and multi-virulent Methicillin-Resistant Staphylococcus aureus (MRSA) and Vancomycin-Resistant Staphylococcus aureus (VRSA) infections, treatment failures and poor prognoses in most cases have been common. Therefore, there is an urgent need for new therapeutic approaches targeting virulence arrays. Our aim is to discover new anti-virulence therapies targeting MRSA and VRSA virulence arrays. Methodology We employed phenotypic, molecular docking, and genetic studies to screen for anti-virulence activities among selected promising compounds: Coumarin, Simvastatin, and Ibuprofen. Results We found that nearly all detected MRSA and VRSA strains exhibited MDR and multi-virulent profiles. The molecular docking results aligned with the phenotypic and genetic assessments of virulence production. Biofilm and hemolysin productions were inhibited, and all virulence genes were downregulated upon treatment with sub-minimum inhibitory concentration (sub-MIC) of these promising compounds. Ibuprofen was the most active compound, exhibiting the highest inhibition and downregulation of virulence gene products. Moreover, in vivo and histopathological studies confirmed these results. Interestingly, we observed a significant decrease in wound area and improvements in re-epithelialization and tissue organization in the Ibuprofen and antimicrobial treated group compared with the group treated with antimicrobial alone. These findings support the idea that a combination of Ibuprofen and antimicrobial drugs may offer a promising new therapy for MRSA and VRSA infections. Conclusion We hope that our findings can be implemented in clinical practice to assist physicians in making the most suitable treatment decisions.
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Affiliation(s)
- Walid Bakeer
- Department of Microbiology and Immunology, Faculty of Pharmacy, Beni-Suef University, Beni-Suef, Egypt
| | - Marwa Gaafar
- Department of Microbiology and Immunology, Faculty of Pharmacy, Beni-Suef University, Beni-Suef, Egypt
- Quality Control Specialist at Egyptian Drug Authority (EDA), Cairo, Egypt
| | - Ahmed O El-Gendy
- Department of Microbiology and Immunology, Faculty of Pharmacy, Beni-Suef University, Beni-Suef, Egypt
| | - Mohamed A El Badry
- Department of Botany and Microbiology, Faculty of Sciences, Al- Azhar University, Cairo, Egypt
| | - Mona G Khalil
- Department of Pharmacology and Toxicology, Faculty of Pharmacy, Modern University for Technology and Information, Cairo, Egypt
| | - Abdallah Tageldein Mansour
- Department of Fish and Animal Production and Aquaculture, College of Agriculture and Food Sciences, King Faisal University, Al-Ahsa, Saudi Arabia
- Department of Fish and Animal Production, Faculty of Agriculture (Saba Basha), Alexandria University, Alexandria, Egypt
| | - Nada K Alharbi
- Department of Biology, College of Science, Princess Nourah bint Abdulrahman University, Riyadh, Saudi Arabia
| | - Heba M R M Selim
- Department of Pharmaceutical Sciences, College of Pharmacy, AlMaarefa University, Riyadh, Saudi Arabia
| | - Mahmoud M Bendary
- Department of Microbiology and Immunology, Faculty of Pharmacy, Port Said University, Port Said, Egypt
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10
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Bonnet E, Maulin L, Senneville E, Castan B, Fourcade C, Loubet P, Poitrenaud D, Schuldiner S, Sotto A, Lavigne JP, Lesprit P. Clinical practice recommendations for infectious disease management of diabetic foot infection (DFI) - 2023 SPILF. Infect Dis Now 2024; 54:104832. [PMID: 37952582 DOI: 10.1016/j.idnow.2023.104832] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/02/2023] [Accepted: 11/03/2023] [Indexed: 11/14/2023]
Abstract
In march 2020, the International Working Group on the Diabetic Foot (IWGDF) published an update of the 2015 guidelines on the diagnosis and management of diabetic foot infection (DFI). While we (the French ID society, SPILF) endorsed some of these recommendations, we wanted to update our own 2006 guidelines and specifically provide informative elements on modalities of microbiological diagnosis and antibiotic treatment (especially first- and second-line regiments, oral switch and duration). The recommendations put forward in the present guidelines are addressed to healthcare professionals managing patients with DFI and more specifically focused on infectious disease management of this type of infection, which clearly needs a multidisciplinary approach. Staging of the severity of the infection is mandatory using the classification drawn up by the IWGDF. Microbiological samples should be taken only in the event of clinical signs suggesting infection in accordance with a strict preliminarily established protocol. Empirical antibiotic therapy should be chosen according to the IWGDF grade of infection and duration of the wound, but must always cover methicillin-sensitive Staphylococcus aureus. Early reevaluation of the patient is a fundamental step, and duration of antibiotic therapy can be shortened in many situations. When osteomyelitis is suspected, standard foot radiograph is the first-line imagery examination and a bone biopsy should be performed for microbiological documentation. Histological analysis of the bone sample is no longer recommended. High dosages of antibiotics are recommended in cases of confirmed osteomyelitis.
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Affiliation(s)
- E Bonnet
- Service des Maladies Infectieuses et Tropicales, CHU Toulouse-Purpan, 31059 Toulouse, France.
| | - L Maulin
- Maladies Infectieuses, CH du Pays d'Aix, 13100 Aix en Provence, France
| | - E Senneville
- Service Universitaire des Maladies Infectieuses, CH Dron, 59200 Tourcoing, France
| | - B Castan
- Service de Médecine Interne et Maladies Infectieuses, CH Périgueux, 24019 Périgueux, France
| | - C Fourcade
- Equipe Mobile d'Infectiologie, Clinique Pasteur, Clinavenir, 31300 Toulouse, France
| | - P Loubet
- Service des Maladies Infectieuses et Tropicales, CHU Caremeau, 30029 Nîmes, France
| | - D Poitrenaud
- Unité Fonctionnelle d'Infectiologie, CH Notre Dame de la Miséricorde, 20000 Ajaccio, France
| | - S Schuldiner
- Service des Maladies Métaboliques et Endocriniennes, CHU Caremeau, 30029 Nîmes, France
| | - A Sotto
- Service des Maladies Infectieuses et Tropicales, CHU Caremeau, 30029 Nîmes, France
| | - J P Lavigne
- Service de Microbiologie et Hygiène Hospitalière, CHU Caremeau, 30029 Nîmes, France
| | - P Lesprit
- Maladies Infectieuses, CHU Grenoble Alpes, 38043, Grenoble, France
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11
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Shahrokh S, Tabatabaee A, Yazdi M, Siavash M. Proportion of toxin and non-toxin virulence factors of Staphylococcus aureus isolates from diabetic foot infection: a systematic review and meta-analysis. BMC Microbiol 2024; 24:1. [PMID: 38172669 PMCID: PMC10763345 DOI: 10.1186/s12866-023-03142-y] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/29/2022] [Accepted: 12/01/2023] [Indexed: 01/05/2024] Open
Abstract
BACKGROUND Staphylococcus aureus isolates are the leading cause of diabetic foot infections (DFIs). Identification of specific virulence factors of S. aureus involved in the pathogenesis of DFIs may help control the infection more effectively. Since the most prevalent virulence factor genes are probably related to the DFI pathogenesis, the aim of this study is to evaluate the proportion of virulence factor genes of S. aureus isolates from DFIs. MATERIALS AND METHODS We conducted a systematic search of PubMed, Embase, Web of Science, and Scopus to identify all articles reporting the proportion of different types of virulence factors of S. aureus isolates from DFI samples. RESULTS Seventeen studies were eligible, in which 1062 S. aureus isolates were obtained from 1948 patients and 2131 DFI samples. Among the toxin virulence factors, hld 100.0% (95% CI: 97.0, 100.0%), hlg 88.0% (95% CI: 58.0, 100.0%), hla 80.0% (95% CI: 31.0, 100.0%), hlgv 79.0% (95% CI: 35.0, 100.0%) and luk-ED 72.0% (95% CI: 42.0, 95.0%) had the highest proportion respectively. Among the genes associated with biofilm formation, both icaA and icaD had the highest proportion 100.0% (95% CI: 95.6, 100.0%). CONCLUSION The results of the present study showed that among the toxin virulence factors, hemolysins (hld, hlg, hla, hlgv) and luk-ED and among the non-toxin virulence factors, icaA and icaD have the greatest proportion in S. aureus isolates from DFIs. These prevalent genes may have the potential to evaluate as virulence factors involved in DFI pathogenesis. Finding these probable virulence factor genes can help control diabetic foot infection more effectively via anti-virulence therapy or preparation of multi-epitope vaccines.
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Affiliation(s)
- Samaneh Shahrokh
- Isfahan Endocrine and Metabolism Research Center, Isfahan University of Medical Sciences, Isfahan, Iran.
| | - Aliye Tabatabaee
- Isfahan Endocrine and Metabolism Research Center, Isfahan University of Medical Sciences, Isfahan, Iran
| | - Maryam Yazdi
- Child Growth, and Development Research Center, Research Institute for Primordial Prevention of Non-Communicable Diseases, Isfahan University of Medical Sciences, Isfahan, Iran
| | - Mansour Siavash
- Isfahan Endocrine and Metabolism Research Center, Isfahan University of Medical Sciences, Isfahan, Iran
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12
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Wang Q, Nurxat N, Zhang L, Liu Y, Wang Y, Zhang L, Zhao N, Dai Y, Jian Y, He L, Wang H, Bae T, Li M, Liu Q. Diabetes mellitus promotes the nasal colonization of high virulent Staphylococcus aureus through the regulation of SaeRS two-component system. Emerg Microbes Infect 2023; 12:2276335. [PMID: 37882148 PMCID: PMC10796126 DOI: 10.1080/22221751.2023.2276335] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/26/2023] [Accepted: 10/23/2023] [Indexed: 10/27/2023]
Abstract
Diabetic foot infections are a common complication of diabetes. Staphylococcus aureus is frequently isolated from diabetic foot infections and commonly colonizes human nares. According to the study, the nasal microbiome analysis revealed that diabetic patients had a significantly altered nasal microbial composition and diversity. Typically, the fasting blood glucose (FBG) level had an impact on the abundance and sequence type (ST) of S. aureus in diabetic patients. We observed that highly virulent S. aureus ST7 strains were more frequently colonized in diabetic patients, especially those with poorly controlled FBG, while ST59 was dominant in healthy individuals. S. aureus ST7 strains were more resistant to human antimicrobial peptides and formed stronger biofilms than ST59 strains. Critically, S. aureus ST7 strains displayed higher virulence compared to ST59 strains in vivo. The dominance of S. aureus ST7 strains in hyperglycemic environment is due to the higher activity of the SaeRS two-component system (TCS). S. aureus ST7 strains outcompeted ST59 both in vitro, and in nasal colonization model in diabetic mice, which was abolished by the deletion of the SaeRS TCS. Our data indicated that highly virulent S. aureus strains preferentially colonize diabetic patients with poorly controlled FBG through SaeRS TCS. Detection of S. aureus colonization and elimination of colonizing S. aureus are critical in the care of diabetic patients with high FBG.
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Affiliation(s)
- Qichen Wang
- Department of Laboratory Medicine, Ren Ji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, People’s Republic of China
| | - Nadira Nurxat
- Department of Laboratory Medicine, Ren Ji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, People’s Republic of China
| | - Lei Zhang
- Department of Vascular Surgery, Yueyang Hospital of Integrated Traditional Chinese and Western Medicine, Shanghai University of Traditional Chinese Medicine, Shanghai, People’s Republic of China
| | - Yao Liu
- Department of Laboratory Medicine, Ren Ji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, People’s Republic of China
| | - Yanan Wang
- Department of Laboratory Medicine, Ren Ji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, People’s Republic of China
| | - Lei Zhang
- Department of Otorhinolaryngology, Head and Neck Surgery, The Second Hospital of Anhui Medical University, Hefei, People’s Republic of China
| | - Na Zhao
- Department of Laboratory Medicine, Ren Ji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, People’s Republic of China
| | - Yingxin Dai
- Department of Laboratory Medicine, Ren Ji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, People’s Republic of China
| | - Ying Jian
- Department of Laboratory Medicine, Ren Ji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, People’s Republic of China
| | - Lei He
- Department of Laboratory Medicine, Ren Ji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, People’s Republic of China
| | - Hua Wang
- Department of Laboratory Medicine, Ren Ji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, People’s Republic of China
| | - Taeok Bae
- Department of Microbiology and Immunology, Indiana University School of Medicine-Northwest, Gary, IN, USA
| | - Min Li
- Department of Laboratory Medicine, Ren Ji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, People’s Republic of China
- Faculty of Medical Laboratory Science, Shanghai Jiao Tong University School of Medicine, Shanghai, People’s Republic of China
| | - Qian Liu
- Department of Laboratory Medicine, Ren Ji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, People’s Republic of China
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13
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Garousi M, MonazamiTabar S, Mirazi H, Farrokhi Z, Khaledi A, Shakerimoghaddam A. Epidemiology of Pseudomonas aeruginosa in diabetic foot infections: a global systematic review and meta-analysis. Germs 2023; 13:362-372. [PMID: 38361543 PMCID: PMC10866166 DOI: 10.18683/germs.2023.1406] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/23/2023] [Revised: 11/09/2023] [Accepted: 12/18/2023] [Indexed: 02/17/2024]
Abstract
Pseudomonas aeruginosa is one of the most common causes of diabetic foot infection globally. This study aimed to determine the global distribution of P. aeruginosa isolated from diabetic foot ulcer infection. PRISMA procedure was used to perform the current systematic review and meta-analysis. The Web of Science, MEDLINE/PubMed, Scopus, and other databases were searched for studies published in English from 2000 to 2022. Data was analyzed using the Comprehensive Meta-Analysis software (CMA). Keywords and MESH phrases included Pseudomonas aeruginosa, diabetic foot ulcer, P. aeruginosa, and diabetic foot infection. As a result of this review, 16.6% of diabetic foot wound infections were caused by P. aeruginosa. About 37.9% of strains were multidrug resistant (MDR). P. aeruginosa infection rates in diabetic foot ulcers ranged from 0.5 to 100% globally. In total, the prevalence rates of P. aeruginosa in diabetic foot ulcer infection from Asia, Africa, and Western countries were reported at 18.5%, 16.3%, and 11.1%, respectively. Data have shown that the prevalence of P. aeruginosa, particularly MDR strains, isolated from diabetic foot ulcer infection was relatively high; inherent resistance to antibiotics is also high; the wound either does not heal or if it does, it will be delayed. Therefore, timely treatment is essential.
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Affiliation(s)
- Mitra Garousi
- MD, Department of Internal Medicine, Faculty of Medical Sciences, Hamedan University of Medical Sciences, Shaheed Fahmideh Ave, postal code: 6517838636, Hamedan, Iran
| | - Sina MonazamiTabar
- MD, Department of Internal Medicine, Faculty of Medical Sciences, Hamedan University of Medical Sciences, Shaheed Fahmideh Ave, postal code: 6517838636, Hamedan, Iran
| | - Hosein Mirazi
- PhD, Department of Biomedical Engineering, Faculty of New Sciences and Technology, University of Tehran, 16 Azar St., Enghelab Sq, postal address: 1417466191, Tehran, Iran
| | - Zahra Farrokhi
- MD, Medical School, Shahid Beheshti University of Medical Sciences, P.O. Box 4739-19395, 7 Floor, Bldg. No.2, SBUMS Sh. Arabi Ave, Tehran, Iran
| | - Azad Khaledi
- PhD, Infectious Diseases Research Center, Kashan University of Medical Sciences, 5 of Qotb –e Ravandi Blvd. P.O. Box: 87155-111, Postal code: 87154, Kashan, Iran
| | - Ali Shakerimoghaddam
- PhD, Medical Biotechnology Research Center, AJA University of Medical Sciences, Etemad Zadeh street, Fatemi-Gharbi Street. P.O. Box: 1411718541, Tehran, Iran
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14
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Ferhaoui N, Tanaka R, Sekizuka T, Kuroda M, Sebaihia M. Whole genome sequencing and pan-genome analysis of Staphylococcus/Mammaliicoccus spp. isolated from diabetic foot ulcers and contralateral healthy skin of Algerian patients. BMC Microbiol 2023; 23:342. [PMID: 37974097 PMCID: PMC10652506 DOI: 10.1186/s12866-023-03087-2] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/01/2023] [Accepted: 10/24/2023] [Indexed: 11/19/2023] Open
Abstract
BACKGROUND Diabetic foot infections (DFIs) are the most common complications of diabetic foot ulcers (DFUs), and a significant cause of lower extremity amputation. In this study we used whole genome sequencing to characterize the clonal composition, virulence and resistance genetic determinants of 58 Staphylococcus/Mammaliicoccus spp. isolates from contralateral healthy skin and DFU from 44 hospitalized patients. RESULTS S. aureus (n = 32) and S. epidermidis (n = 10) isolates were recovered from both DFUs and healthy skin, whereas, S. haemolyticus (n = 8), M. sciuri (n = 1), S. hominis (n = 1) and S. simulans (n = 3) were recovered exclusively from healthy skin. In contrast, S. caprae (n = 2) and S. saprophyticus (n = 1) were recovered only from DFUs. Among S. aureus isolates, MRSA were present with high prevalence (27/32, 84.4%), 18 of which (66.7%) were from DFUs and 9 (33.3%) from healthy skin. In contrast, the coagulase-negative Staphylococcus (CoNS)/Mammaliicoccus isolates (n = 26), in particular S. epidermidis and S. haemolyticus were more prevalent in healthy skin, (10/26, 38.5%) and (8/26, 30.8%), respectively. MLST, spa and SCCmec typing classified the 32 S. aureus isolates into 6 STs, ST672, ST80, ST241, ST1, ST97, ST291 and 4 unknown STs (STNF); 8 spa types, t044, t037, t3841, t1247, t127, t639, t937 and t9432 and 2 SCCmec types, type IV and type III(A). Among CoNS, the S. epidermidis isolates belonged to ST54, ST35 and ST640. S. haemolyticus belonged to ST3, ST25, ST29, ST1 and ST56. The sole M. sciuri isolate was found to carry an SCCmec type III(A). A wide range of virulence genes and antimicrobial resistance genes were found among our isolates, with varying distribution between species or STs. The pan-genome analysis revealed a highly clonal population of Staphylococcus isolates, particularly among S. aureus isolates. Interestingly, the majority of S. aureus isolates including MRSA, recovered from the healthy skin and DFUs of the same patient belonged to the same clone and exhibited similar virulence/resistance genotype. CONCLUSIONS Our study provides clinically relevant information on the population profile, virulence and antibiotic resistance of Staphylococcus/Mammaliicoccus spp. in DFIs, which could serve as a basis for further studies on these as well as other groups of pathogens associated with DFIs.
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Affiliation(s)
- Nerdjes Ferhaoui
- Laboratory of Molecular Biology, Genomics and Bioinformatics, Department of Biology, Faculty of Nature and Life Sciences, University Hassiba Benbouali, Chlef, Algeria
| | - Rina Tanaka
- Pathogen Genomics Center, National Institute of Infectious Diseases (NIID), Tokyo, Japan
| | - Tsuyoshi Sekizuka
- Pathogen Genomics Center, National Institute of Infectious Diseases (NIID), Tokyo, Japan
| | - Makoto Kuroda
- Pathogen Genomics Center, National Institute of Infectious Diseases (NIID), Tokyo, Japan
| | - Mohammed Sebaihia
- Laboratory of Molecular Biology, Genomics and Bioinformatics, Department of Biology, Faculty of Nature and Life Sciences, University Hassiba Benbouali, Chlef, Algeria.
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15
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Campbell AE, McCready-Vangi AR, Uberoi A, Murga-Garrido SM, Lovins VM, White EK, Pan JTC, Knight SAB, Morgenstern AR, Bianco C, Planet PJ, Gardner SE, Grice EA. Variable staphyloxanthin production by Staphylococcus aureus drives strain-dependent effects on diabetic wound-healing outcomes. Cell Rep 2023; 42:113281. [PMID: 37858460 PMCID: PMC10680119 DOI: 10.1016/j.celrep.2023.113281] [Citation(s) in RCA: 17] [Impact Index Per Article: 8.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/21/2022] [Revised: 08/24/2023] [Accepted: 09/28/2023] [Indexed: 10/21/2023] Open
Abstract
Strain-level variation in Staphylococcus aureus is a factor that contributes to disease burden and clinical outcomes in skin disorders and chronic wounds. However, the microbial mechanisms that drive these variable host responses are poorly understood. To identify mechanisms underlying strain-specific outcomes, we perform high-throughput phenotyping screens on S. aureus isolates cultured from diabetic foot ulcers. Isolates from non-healing wounds produce more staphyloxanthin, a cell membrane pigment. In murine diabetic wounds, staphyloxanthin-producing isolates delay wound closure significantly compared with staphyloxanthin-deficient isolates. Staphyloxanthin promotes resistance to oxidative stress and enhances bacterial survival in neutrophils. Comparative genomic and transcriptomic analysis of genetically similar clinical isolates with disparate staphyloxanthin phenotypes reveals a mutation in the sigma B operon, resulting in marked differences in stress response gene expression. Our work illustrates a framework to identify traits that underlie strain-level variation in disease burden and suggests more precise targets for therapeutic intervention in S. aureus-positive wounds.
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Affiliation(s)
- Amy E Campbell
- Departments of Dermatology and Microbiology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA
| | - Amelia R McCready-Vangi
- Departments of Dermatology and Microbiology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA
| | - Aayushi Uberoi
- Departments of Dermatology and Microbiology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA
| | - Sofía M Murga-Garrido
- Departments of Dermatology and Microbiology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA
| | - Victoria M Lovins
- Departments of Dermatology and Microbiology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA
| | - Ellen K White
- Departments of Dermatology and Microbiology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA
| | - Jamie Ting-Chun Pan
- Departments of Dermatology and Microbiology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA
| | - Simon A B Knight
- Departments of Dermatology and Microbiology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA
| | - Alexis R Morgenstern
- Departments of Dermatology and Microbiology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA
| | - Colleen Bianco
- Division of Infectious Disease, Department of Pediatrics, The Children's Hospital of Philadelphia, Philadelphia, PA 19104, USA
| | - Paul J Planet
- Division of Infectious Disease, Department of Pediatrics, The Children's Hospital of Philadelphia, Philadelphia, PA 19104, USA; Departments of Pediatrics and Microbiology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA
| | - Sue E Gardner
- College of Nursing, University of Iowa, Iowa City, IA 52242, USA
| | - Elizabeth A Grice
- Departments of Dermatology and Microbiology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA.
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16
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Mutti M, Moreno DS, Restrepo-Córdoba M, Visram Z, Resch G, Corsini L. Phage activity against Staphylococcus aureus is impaired in plasma and synovial fluid. Sci Rep 2023; 13:18204. [PMID: 37875544 PMCID: PMC10598271 DOI: 10.1038/s41598-023-45405-8] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/10/2023] [Accepted: 10/19/2023] [Indexed: 10/26/2023] Open
Abstract
S. aureus is a pathogen that frequently causes severe morbidity and phage therapy is being discussed as an alternative to antibiotics for the treatment of S. aureus infections. In this in vitro and animal study, we demonstrated that the activity of anti-staphylococcal phages is severely impaired in 0.5% plasma or synovial fluid. Despite phage replication in these matrices, lysis of the bacteria was slower than phage propagation, and no reduction of the bacterial population was observed. The inhibition of the phages associated with a reduction in phage adsorption, quantified to 99% at 10% plasma. S. aureus is known to bind multiple coagulation factors, resulting in the formation of aggregates and blood clots that might protect the bacterium from the phages. Here, we show that purified fibrinogen at a sub-physiological concentration of 0.4 mg/ml is sufficient to impair phage activity. In contrast, dissolution of the clots by tissue plasminogen activator (tPA) partially restored phage activity. Consistent with these in vitro findings, phage treatment did not reduce bacterial burdens in a neutropenic mouse S. aureus thigh infection model. In summary, phage treatment of S. aureus infections inside the body may be fundamentally challenging, and more investigation is needed prior to proceeding to in-human trials.
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Affiliation(s)
| | | | | | | | - Grégory Resch
- Center for Research and Innovation in Clinical Pharmaceutical Sciences (CRISP), Lausanne Hospital (CHUV), Lausanne, Switzerland
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17
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Gehrke AKE, Giai C, Gómez MI. Staphylococcus aureus Adaptation to the Skin in Health and Persistent/Recurrent Infections. Antibiotics (Basel) 2023; 12:1520. [PMID: 37887220 PMCID: PMC10604630 DOI: 10.3390/antibiotics12101520] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/06/2023] [Revised: 10/03/2023] [Accepted: 10/04/2023] [Indexed: 10/28/2023] Open
Abstract
Staphylococcus aureus is a microorganism with an incredible capability to adapt to different niches within the human body. Approximately between 20 and 30% of the population is permanently but asymptomatically colonized with S. aureus in the nose, and another 30% may carry S. aureus intermittently. It has been established that nasal colonization is a risk factor for infection in other body sites, including mild to severe skin and soft tissue infections. The skin has distinct features that make it a hostile niche for many bacteria, therefore acting as a strong barrier against invading microorganisms. Healthy skin is desiccated; it has a low pH at the surface; the upper layer is constantly shed to remove attached bacteria; and several host antimicrobial peptides are produced. However, S. aureus is able to overcome these defenses and colonize this microenvironment. Moreover, this bacterium can very efficiently adapt to the stressors present in the skin under pathological conditions, as it occurs in patients with atopic dermatitis or suffering chronic wounds associated with diabetes. The focus of this manuscript is to revise the current knowledge concerning how S. aureus adapts to such diverse skin conditions causing persistent and recurrent infections.
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Affiliation(s)
- Ana-Katharina E. Gehrke
- Centro de Estudios Biomédicos, Básicos, Aplicados y Desarrollo (CEBBAD), Departamento de Investigaciones Biomédicas y Biotecnológicas, Universidad Maimónides, Buenos Aires C1405BCK, Argentina;
- Consejo Nacional de Investigaciones Científicas y Técnicas (CONICET), Buenos Aires C1425FQB, Argentina
| | - Constanza Giai
- Instituto de Histología y Embriología de Mendoza, Universidad Nacional de Cuyo—(UNCuyo) CONICET, Mendoza M5502JMA, Argentina;
- Facultad de Ciencias Médicas, Universidad Nacional de Cuyo, Mendoza M5502JMA, Argentina
- Facultad de Farmacia y Bioquímica, Universidad Juan Agustín Maza, Mendoza C1006ACC, Argentina
| | - Marisa I. Gómez
- Centro de Estudios Biomédicos, Básicos, Aplicados y Desarrollo (CEBBAD), Departamento de Investigaciones Biomédicas y Biotecnológicas, Universidad Maimónides, Buenos Aires C1405BCK, Argentina;
- Consejo Nacional de Investigaciones Científicas y Técnicas (CONICET), Buenos Aires C1425FQB, Argentina
- Departamento de Microbiología, Parasitología e Inmunología, Facultad de Medicina, Universidad de Buenos Aires, Buenos Aires C1121A6B, Argentina
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18
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Battaglia M, Garrett-Sinha LA. Staphylococcus xylosus and Staphylococcus aureus as commensals and pathogens on murine skin. Lab Anim Res 2023; 39:18. [PMID: 37533118 PMCID: PMC10394794 DOI: 10.1186/s42826-023-00169-0] [Citation(s) in RCA: 9] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/19/2023] [Revised: 07/19/2023] [Accepted: 07/24/2023] [Indexed: 08/04/2023] Open
Abstract
Skin ulcers, skin dermatitis and skin infections are common phenomena in colonies of laboratory mice and are often found at increased prevalence in certain immunocompromised strains. While in many cases these skin conditions are mild, in other cases they can be severe and lead to animal morbidity. Furthermore, the presence of skin infections and ulcerations can complicate the interpretation of experimental protocols, including those examining immune cell activation. Bacterial species in the genus Staphylococcus are the most common pathogens recovered from skin lesions in mice. In particular, Staphylococcus aureus and Staphylococcus xylosus have both been implicated as pathogens on murine skin. Staphylococcus aureus is a well-known pathogen of human skin, but S. xylosus skin infections in humans have not been described, indicating that there is a species-specific difference in the ability of S. xylosus to serve as a skin pathogen. The aim of this review is to summarize studies that link S. aureus and S. xylosus to skin infections of mice and to describe factors involved in their adherence to tissue and their virulence. We discuss potential differences in mouse and human skin that might underlie the ability of S. xylosus to act as a pathogen on murine skin, but not human skin. Finally, we also describe mouse mutants that have shown increased susceptibility to skin infections with staphylococcal bacteria. These mutants point to pathways that are important in the control of commensal staphylococcal bacteria. The information here may be useful to researchers who are working with mouse strains that are prone to skin infections with staphylococcal bacteria.
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Affiliation(s)
- Michael Battaglia
- Department of Biochemistry, Jacobs School of Medicine and Biomedical Sciences, State University of New York at Buffalo, Buffalo, NY, 14203, USA
| | - Lee Ann Garrett-Sinha
- Department of Biochemistry, Jacobs School of Medicine and Biomedical Sciences, State University of New York at Buffalo, Buffalo, NY, 14203, USA.
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Wu Y, Chen T, Wang Y, Huang M, Wang Y, Luo Z. New insight into the virulence and inflammatory response of Staphylococcus aureus strains isolated from diabetic foot ulcers. Front Cell Infect Microbiol 2023; 13:1234994. [PMID: 37577369 PMCID: PMC10416727 DOI: 10.3389/fcimb.2023.1234994] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/05/2023] [Accepted: 07/14/2023] [Indexed: 08/15/2023] Open
Abstract
Staphylococcus aureus strains isolated from diabetic foot ulcers (DFUs) have less virulence, but still cause severe infections. Furthermore, hypovirulent S. aureus strains appear to be localized in the deep tissues of diabetic foot osteomyelitis, indicating that the unique environment within DFUs affects the pathogenicity of S. aureus. In this study, the cell-free culture medium (CFCM) of S. aureus strains isolated from DFUs exhibited higher cytotoxicity to human erythrocytes than those isolated from non-diabetic patients with sepsis or wounds. Among these S. aureus strains isolated from DFUs, β-toxin negative strains have less virulence than β-toxin positive strains, but induced a higher expression of inflammatory cytokines. Our study and previous studies have shown that the synergistic effect of phenol-soluble modulin α and β-toxin contributes to the higher hemolytic activity of β-toxin positive strains. However, lysis of human erythrocytes by the CFCM of β-toxin negative strains was greatly inhibited by an autolysin inhibitor, sodium polyanethole sulfonate (SPS). A high level of glucose greatly reduced the hemolytic activity of S. aureus, but promoted the expression of interleukin-6 (IL-6) in human neutrophils. However, 5 mM glucose or glucose-6-phosphate (G6P) increased the hemolytic activity of SA118 (a β-toxin negative strain) isolated from DFUs. Additionally, patients with DFUs with growth of S. aureus had lower level of serum IL-6 than those with other bacteria, and the CFCM of S. aureus strains significantly reduced lipopolysaccharide-induced IL-6 expression in human neutrophils. Therefore, the virulence and inflammatory response of S. aureus strains isolated from DFUs are determined by the levels of glucose and its metabolites, which may explain why it is the predominant bacteria isolated from DFUs.
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Affiliation(s)
- Yuan Wu
- Department of Laboratory Medicine, The Third Xiangya Hospital, Central South University, Changsha, China
| | - Ti Chen
- Department of Laboratory Medicine, The Third Xiangya Hospital, Central South University, Changsha, China
| | - Yanle Wang
- Department of Laboratory Medicine, The Third Xiangya Hospital, Central South University, Changsha, China
| | - Mao Huang
- Department of Laboratory Medicine, Xiangya School of Medicine, Central South University, Changsha, China
| | - Yurong Wang
- Department of Laboratory Medicine, Xiangya School of Medicine, Central South University, Changsha, China
| | - Zhen Luo
- Department of Laboratory Medicine, The Third Xiangya Hospital, Central South University, Changsha, China
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Rajab AAH, Hegazy WAH. What’s old is new again: Insights into diabetic foot microbiome. World J Diabetes 2023; 14:680-704. [PMID: 37383589 PMCID: PMC10294069 DOI: 10.4239/wjd.v14.i6.680] [Citation(s) in RCA: 18] [Impact Index Per Article: 9.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/26/2022] [Revised: 02/20/2023] [Accepted: 04/10/2023] [Indexed: 06/14/2023] Open
Abstract
Diabetes is a chronic disease that is considered one of the most stubborn global health problems that continues to defy the efforts of scientists and physicians. The prevalence of diabetes in the global population continues to grow to alarming levels year after year, causing an increase in the incidence of diabetes complications and health care costs all over the world. One major complication of diabetes is the high susceptibility to infections especially in the lower limbs due to the immunocompromised state of diabetic patients, which is considered a definitive factor in all cases. Diabetic foot infections continue to be one of the most common infections in diabetic patients that are associated with a high risk of serious complications such as bone infection, limb amputations, and life-threatening systemic infections. In this review, we discussed the circumstances associated with the high risk of infection in diabetic patients as well as some of the most commonly isolated pathogens from diabetic foot infections and the related virulence behavior. In addition, we shed light on the different treatment strategies that aim at eradicating the infection.
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Affiliation(s)
- Azza A H Rajab
- Department of Microbiology and Immunology, Faculty of Pharmacy, Zagazig University, Zagzig 44511, Egypt
| | - Wael A H Hegazy
- Department of Microbiology and Immunology, Faculty of Pharmacy, Zagazig University, Zagzig 44511, Egypt
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21
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Grealy L, Wilson P, Gillen C, Duffy É, Healy ML, Daly B, Polyzois I, Van Harten M, Dougall A, Brennan GI, Coleman DC, McManus BA. Immersion of debrided diabetic foot ulcer (DFU) tissue in electrochemically generated pH neutral hypochlorous acid significantly reduces the microbial bioburden: whole-genome sequencing of Staphylococcus aureus, the most prevalent species recovered. J Hosp Infect 2023:S0195-6701(23)00179-2. [PMID: 37308064 DOI: 10.1016/j.jhin.2023.06.006] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/22/2023] [Revised: 06/08/2023] [Accepted: 06/08/2023] [Indexed: 06/14/2023]
Abstract
BACKGROUND Diabetic foot ulcer infections (DFUIs) are the leading cause of lower limb amputations, mediated predominantly by Staphylococcus aureus. pH neutral electrochemically-generated hypochlorous acid (anolyte) is a non-toxic, microbiocidal agent with significant potential for wound disinfection. AIMS To investigate both the effectiveness of anolyte for microbial bioburden reduction in debrided ulcer tissues and the population of resident S. aureus. METHODS Fifty-one debrided tissues from 30 people with type II diabetes were aliquoted by wet weight and immersed in 1 or 10 ml volumes of anolyte (200 parts per million) or saline for three min. Microbial loads recovered were determined in colony forming units/g (CFU/g) of tissue following aerobic, anaerobic and staphylococcal-selective culture. Bacterial species were identified and 50 S. aureus isolates from 30 tissues underwent whole-genome sequencing (WGS). FINDINGS The ulcers were predominantly superficial, lacking signs of infection (39/51, 76.5%). Of the 42/51 saline-treated tissues yielding ≥105 CFU/g, a microbial threshold reported to impede wound-healing, only 4/42 (9.5%) were clinically-diagnosed DFUIs. Microbial loads from anolyte-treated tissues were significantly lower than saline-treated tissues using 1 ml (1065-fold, 2.0 log) and 10 ml (8216-fold, 2.1 log) immersion volumes (p<0.0005). Staphylococcus aureus was the predominant species recovered (44/51, 86.3%) and 50 isolates underwent WGS. All were meticillin-susceptible and comprised 12 sequence types (STs), predominantly ST1, ST5 and ST15. Whole-genome multilocus sequence typing identified three clusters of closely related isolates from 10 patients indicating inter-patient transmission. CONCLUSIONS Short immersions of debrided ulcer tissue in anolyte significantly reduced microbial bioburden: a potential novel DFUI treatment.
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Affiliation(s)
- Liam Grealy
- Microbiology Research Unit, Division of Oral Biosciences, Dublin Dental University Hospital, The University of Dublin, Trinity College Dublin, Dublin, Ireland
| | - Pauline Wilson
- Department of Endocrinology & Diabetes, St. James's Hospital, Dublin, Ireland
| | - Corey Gillen
- Department of Endocrinology & Diabetes, St. James's Hospital, Dublin, Ireland
| | - Éilish Duffy
- Microbiology Research Unit, Division of Oral Biosciences, Dublin Dental University Hospital, The University of Dublin, Trinity College Dublin, Dublin, Ireland
| | - Marie-Louise Healy
- Department of Endocrinology & Diabetes, St. James's Hospital, Dublin, Ireland
| | - Blánaid Daly
- Division of Public and Child Dental Health, Dublin Dental University Hospital, The University of Dublin, Trinity College Dublin, Dublin, Ireland
| | - Ioannis Polyzois
- Division of Restorative Dentistry and Periodontology, Dublin Dental University Hospital, The University of Dublin, Trinity College Dublin, Dublin, Ireland
| | - Maria Van Harten
- Division of Public and Child Dental Health, Dublin Dental University Hospital, The University of Dublin, Trinity College Dublin, Dublin, Ireland
| | - Alison Dougall
- Division of Public and Child Dental Health, Dublin Dental University Hospital, The University of Dublin, Trinity College Dublin, Dublin, Ireland
| | - Gráinne I Brennan
- National MRSA Reference Laboratory, St. James's Hospital, Dublin, Ireland
| | - David C Coleman
- Microbiology Research Unit, Division of Oral Biosciences, Dublin Dental University Hospital, The University of Dublin, Trinity College Dublin, Dublin, Ireland
| | - Brenda A McManus
- Microbiology Research Unit, Division of Oral Biosciences, Dublin Dental University Hospital, The University of Dublin, Trinity College Dublin, Dublin, Ireland.
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Kmiha S, Jouini A, Zerriaa N, Hamrouni S, Thabet L, Maaroufi A. Methicillin-Resistant Staphylococcusaureus Strains Isolated from Burned Patients in a Tunisian Hospital: Molecular Typing, Virulence Genes, and Antimicrobial Resistance. Antibiotics (Basel) 2023; 12:1030. [PMID: 37370349 DOI: 10.3390/antibiotics12061030] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/23/2023] [Revised: 05/25/2023] [Accepted: 05/30/2023] [Indexed: 06/29/2023] Open
Abstract
Methicillin-resistant Staphylococcus aureus (MRSA) is one of the major causes of a variety of infections in hospitals and the community. Their spread poses a serious public health problem worldwide. Nevertheless, in Tunisia and other African countries, very little molecular typing data on MRSA strains is currently available. In our study, a total of 64 MRSA isolates were isolated from clinical samples collected from burned patients hospitalized in the Traumatology and Burns Center of Ben Arous in Tunisia. The identification of the collection was based on conventional methods (phenotypic and molecular characterization). The characterization of the genetic support for methicillin resistance was performed by amplification of the mecA gene by polymerase chain reaction (PCR), which revealed that 78.12% of S. aureus harbors the gene. The resistance of all the collection to different antibiotic families was studied. Indeed, the analysis of strain antibiotic susceptibility confirmed their multi-resistant phenotype, with high resistance to ciprofloxacin, gentamicin, penicillin, erythromycin, and tetracycline. The resistance to the last three antibiotics was conferred by the blaZ gene (73.43%), the erm(C) gene (1.56%), the msr(A) gene (6.25%), and tet(M) gene (7.81%), respectively. The clonal diversity of these strains was studied by molecular typing of the accessory gene regulator (agr) system, characterization of the SCCmec type, and spa-typing. The results revealed the prevalence of agr types II and III groups, the SCCmec type III and II cassettes, and the dominance of spa type t233. The characterization of the eight enterotoxins genes, the Panton-Valentine leukocidin and the toxic shock syndrome toxin, was determined by PCR. The percentage of virulence genes detected was for enterotoxins (55%), tst (71.88%), leukocidin E/D (79.69%), and pvl (1.56%) factors. Furthermore, our results revealed that the majority of the strains harbor IEC complex genes (94%) with different types. Our findings highlighted the emergence of MRSA strains with a wide variety of toxins, leukocidin associated with resistance genes, and specific genetic determinants, which could constitute a risk of their spread in hospitals and the environment and complicate infection treatment.
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Affiliation(s)
- Souhir Kmiha
- Laboratory of Epidemiology and Veterinary Microbiology, Group of Bacteriology and Biotechnology Development, Pasteur Institute of Tunis, University of Tunis El Manar, Tunis 2092, Tunisia
| | - Ahlem Jouini
- Laboratory of Epidemiology and Veterinary Microbiology, Group of Bacteriology and Biotechnology Development, Pasteur Institute of Tunis, University of Tunis El Manar, Tunis 2092, Tunisia
| | - Nahawend Zerriaa
- Laboratory of Epidemiology and Veterinary Microbiology, Group of Bacteriology and Biotechnology Development, Pasteur Institute of Tunis, University of Tunis El Manar, Tunis 2092, Tunisia
| | - Safa Hamrouni
- Laboratory of Epidemiology and Veterinary Microbiology, Group of Bacteriology and Biotechnology Development, Pasteur Institute of Tunis, University of Tunis El Manar, Tunis 2092, Tunisia
| | - Lamia Thabet
- Laboratory of Microbiology, Center for Traumatology and Major Burns, Rue du 1er Mai, Ben Arous 2013, Tunisia
| | - Abderrazak Maaroufi
- Laboratory of Epidemiology and Veterinary Microbiology, Group of Bacteriology and Biotechnology Development, Pasteur Institute of Tunis, University of Tunis El Manar, Tunis 2092, Tunisia
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Liu Y, Zhang X, Yang L, Zhou S, Li Y, Shen Y, Lu S, Zhou J, Liu Y. Proteomics and transcriptomics explore the effect of mixture of herbal extract on diabetic wound healing process. PHYTOMEDICINE : INTERNATIONAL JOURNAL OF PHYTOTHERAPY AND PHYTOPHARMACOLOGY 2023; 116:154892. [PMID: 37267693 DOI: 10.1016/j.phymed.2023.154892] [Citation(s) in RCA: 11] [Impact Index Per Article: 5.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Received: 02/06/2023] [Revised: 04/28/2023] [Accepted: 05/16/2023] [Indexed: 06/04/2023]
Abstract
BACKGROUND The annual incidence of diabetic foot ulcers (DFUs) has been reported to vary from 0.2% to 11% in diabetes-specific clinical settings and less than 0.1% to 8% in community- and population-based cohorts. According to the International Diabetes Foundation, approximately 40 million to 60 million people worldwide are affected by DFUs, and a recent meta-analysis indicates a global prevalence of 6.3% among adults with diabetes, or about 33 million individuals. The cost of diabetes care is significant, amounting to $273 billion in direct and $90 billion in indirect expenses annually, in America. Foot complications in diabetes care excess annual expenditures ranging from 50% to 200% above the baseline cost of diabetes-related care. The cost of advanced-stage ulcers can be more than $50,000 per wound episode, and the direct expenses of major amputation are even higher. DFUs can be treated using various methods, including wound dressings, antibiotics, pressure-off loading, skin substitutes, stem cells, debridement, topical oxygen therapy, gene therapy and growth factors. For severe DFUs patients are at risk of amputation if treatment is not timely or appropriate. Amputating limbs not only causes physical pain to patients, but also brings economic burden due to lost productivity, and decreased employment linked to DFUs. Currently, long-term use of local antibiotics in clinical practice is prone to induce drug resistance, while growth factors do not effectively inhibit bacterial growth and control inflammation in wounds. Stem cell and gene therapies are still in the experimental stage. The method of local debridement combined with negative pressure therapy is expensive. Therefore, we urgently need an affordable, non-surgical method to treat diabetic ulcers. Extracts of bark of Bauhinia purpurea, Paeoniae rubrae, Angelica dahurica (Hoffm.) Benth. & Hook.f. ex Franch. & Sav. (Hoffm.) Benth. & Hook.f. ex Franch. & Sav., Acorus calamus L, and Radix Angelicae biseratae have been used as traditional remedies to treat inflammation-related diseases and cutaneous wounds due to their anti-inflammatory properties and their ability to promote vascular renewal. However, there have been few studies on the mixture of these five herbal extracts on diabetic wound healing. PURPOSE This study was designed to assess the healing effect of a mixture of five aforementioned herbal extracts on diabetic ulcer wounds in rats, and to reveal the potential mechanisms behind any potential wound healing using transcriptomics and proteomics. STUDY DESIGN We designed the experiment to explore the effects of five herbal extracts on diabetic wound healing process through in vivo experiments and to investigate the underlying mechanisms through proteomics and transcriptomics. METHODS We used a mixture of five aforementioned herbal extract to treat rat model of diabetic established by intraperitoneal injection of streptozotocin, and a 2 × 2 cm round full-thickness skin defect was created on the back of the rat. Staphylococcus aureus (1 ml of 1.5 × 109 cfu/ml) was evenly applied to the wound. The wound was then observed for 72 h. The infected ulcer model of diabetic rats was considered to be successfully established if the wound was found to be infected with S. aureus. According to different medications, the rats were divided into three groups, namely mixture of herbal extract (MHE), Kangfuxin solution (KFS) and control (Ctrl). The effects of the medicine on wound healing were observed. HE staining and Masson staining were performed to evaluate the histopathological changes and collagen synthesis. IHC staining was used to assess the neovascularization, and M2 macrophage proliferation was determined by immunofluorescence staining. Proteomic and transcriptomic studies were performed to explore potential mechanism of five herbal extracts to promote wound healing. UHPLC-QE-MS was performed to identify the chemical composition of mixture of herbal extract. RESULTS The study show that the mixed herbal extract promotes angiogenesis, proliferation of M2 macrophages, and collagen synthesis. Transcriptomics showed that rno-miR-1298, rno-miR-144-5p, and rno-miR-92a-1-5p are vital miRNAs which also play a significant role in role in regulating wound healing. Proteomics results showed that the following proteins were important in wounds treated with MHE: Rack1, LOC100362366, Cops2, Cops6, Eif4e, Eif3c, Rpl12, Srp54, Rpl13 and Lsm7. Autophagy, PI3-Akt and mTOR signaling pathways were enriched after treatment with MHE compared to other groups. CONCLUSION Herein, we have shown that MHE containing extracts of bark of Bauhinia purpurea, P. rubrae, A. dahurica (Hoffm.) Benth. & Hook.f. ex Franch. & Sav., A. calamus L, and R. A. biseratae has significant wound healing effects in the diabetic ulcer wound rat model. These results suggest that local application of MHE in diabetic wounds can accelerate the wound healing process. Moreover, in vivo experiments revealed that the diabetic wound healing process was primarily mediated by angiogenesis and M2 macrophage transition. Therefore, this study may provide a promising and non-surgical therapeutic strategy to accelerate diabetic wound healing, thereby decreasing the number of limb amputations in diabetic patients.
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Affiliation(s)
- Yang Liu
- Inner Mongolia Medical University, Hohhot, Inner Mongolia Autonomous Region, 010107, China; Department of Plastic Surgery, The Third Xiangya Hospital of Central South University, Changsha, Hunan, 410013, China
| | - Xi Zhang
- The First Affiliated Hospital of Hunan University of Chinese Medicine, Changsha, 410007, China
| | - Liping Yang
- Inner Mongolia Medical University, Hohhot, Inner Mongolia Autonomous Region, 010107, China
| | - Shuai Zhou
- Inner Mongolia Medical University, Hohhot, Inner Mongolia Autonomous Region, 010107, China
| | - Yuewei Li
- Inner Mongolia Medical University, Hohhot, Inner Mongolia Autonomous Region, 010107, China
| | - Yiyu Shen
- Department of Plastic Surgery, The Third Xiangya Hospital of Central South University, Changsha, Hunan, 410013, China
| | - Shengli Lu
- Department of Plastic Surgery, The Third Xiangya Hospital of Central South University, Changsha, Hunan, 410013, China
| | - Jianda Zhou
- Department of Plastic Surgery, The Third Xiangya Hospital of Central South University, Changsha, Hunan, 410013, China.
| | - Yu Liu
- Inner Mongolia Medical University, Hohhot, Inner Mongolia Autonomous Region, 010107, China; Hunan University of Chinese Medicine, Changsha, 410007, China.
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Shimamura Y, Noaki R, Oura Y, Ichikawa K, Kan T, Masuda S. Regulation of Staphylococcal Enterotoxin-Induced Inflammation in Spleen Cells from Diabetic Mice by Polyphenols. Microorganisms 2023; 11:microorganisms11041039. [PMID: 37110462 PMCID: PMC10143252 DOI: 10.3390/microorganisms11041039] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/08/2023] [Revised: 03/31/2023] [Accepted: 04/14/2023] [Indexed: 04/29/2023] Open
Abstract
Patients with diabetes are known to be more susceptible to infections following the establishment of Staphylococcus aureus in their nasal passages and on their skin. The present study evaluated the effects of staphylococcal enterotoxin A (SEA) on the immune responses of spleen cells derived from diabetic mice, and examined the effects of polyphenols, catechins, and nobiletin on inflammation-related gene expression associated with the immune response. (-)-Epigallocatechin gallate (EGCG), possessing hydroxyl groups, interacted with SEA, whereas nobiletin, possessing methyl groups, did not interact with SEA. The exposure of spleen cells derived from diabetic mice to SEA enhanced the expression of interferon gamma, suppressor of cytokine signaling 1, signal transducer and activator of transcription 3, interferon-induced transmembrane protein 3, Janus kinase 2, and interferon regulatory factor 3, suggesting that SEA sensitivity is variable in the development of diabetes. Both EGCG and nobiletin changed the expression of genes related to SEA-induced inflammation in spleen cells, suggesting that they inhibit inflammation through different mechanisms. These results may lead to a better understanding of the SEA-induced inflammatory response during diabetogenesis, and the establishment of methods to control these effects with polyphenols.
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Affiliation(s)
- Yuko Shimamura
- School of Food and Nutritional Sciences, University of Shizuoka, 52-1 Yada, Suruga-ku, Shizuoka 422-8526, Japan
| | - Rina Noaki
- School of Food and Nutritional Sciences, University of Shizuoka, 52-1 Yada, Suruga-ku, Shizuoka 422-8526, Japan
| | - Yukino Oura
- School of Food and Nutritional Sciences, University of Shizuoka, 52-1 Yada, Suruga-ku, Shizuoka 422-8526, Japan
| | - Kenya Ichikawa
- School of Food and Nutritional Sciences, University of Shizuoka, 52-1 Yada, Suruga-ku, Shizuoka 422-8526, Japan
| | - Toshiyuki Kan
- Department of Synthetic Organic & Medicinal Chemistry, School of Pharmaceutical Sciences, University of Shizuoka, 52-1 Yada, Suruga-ku, Shizuoka 422-8526, Japan
| | - Shuichi Masuda
- School of Food and Nutritional Sciences, University of Shizuoka, 52-1 Yada, Suruga-ku, Shizuoka 422-8526, Japan
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Wang Y, Pi Y, Hu L, Peng Z, Hu H, Zhao J, Zhou Y, Wang D. Proteomic analysis of foot ulcer tissue reveals novel potential therapeutic targets of wound healing in diabetic foot ulcers. Comput Biol Med 2023; 159:106858. [PMID: 37087778 DOI: 10.1016/j.compbiomed.2023.106858] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/25/2022] [Revised: 02/13/2023] [Accepted: 03/30/2023] [Indexed: 04/25/2023]
Abstract
Foot ulcers are a common complication of diabetes mellitus, which is associated with high morbidity and mortality among diabetic patients. The present study aims to investigate novel wound healing pathways in diabetic foot ulcers (DFU) through proteomics and a network pharmacology analysis. Tandem mass tag (TMT) labeled quantitative proteomics method was performed to evaluate the protein expression profile in wound tissues from healthy controls (HC) and DFU. Kyoto Encyclopedia of Genes (KEGG) and Genomes enrichment analysis (GO) was conducted based on differentially expressed proteins (DEPs) to discover the potential pathways associated with DFU. Western blot analysis was used to confirm the probable DFU-related targets. Proteomics analysis discovered 509 DEPs (248 upregulated and 261 downregulated proteins). Go and KEGG further evaluated the DEPs to discover the DFU-related pathways. According to network pharmacology study, three main targets (metalloproteinase 9 (MMP9), Fatty acid-binding protein 5 (FABP5), and integrin subunit alpha M (ITGAM)) play crucial roles in signaling pathways. Staphylococcus aureus infection and leukocyte transendothelial migration pathways significantly enriched in DFU. In addition, it was confirmed that three critical targets were elevated in diabetes mouse wound tissues. The study confirmed the presence of protein alterations in the wound-healing process of DFU mice and may provide fresh insights into the molecular mechanisms driving DFU.
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Affiliation(s)
- Yanling Wang
- The First Hospital of Changsha, Changsha, 410005, China; The Affiliated Changsha Hospital of Xiangya School of Medicine, Central South University, Changsha, 410008, China; Changsha Maternal and Child Health Hospital Affiliated to Hunan Normal University, Changsha, 410007, China
| | - Yinzhen Pi
- The First Hospital of Changsha, Changsha, 410005, China; The Affiliated Changsha Hospital of Xiangya School of Medicine, Central South University, Changsha, 410008, China
| | - Li Hu
- The First Hospital of Changsha, Changsha, 410005, China; The Affiliated Changsha Hospital of Xiangya School of Medicine, Central South University, Changsha, 410008, China
| | - Zhihong Peng
- National & Local Joint Engineering Research Center of High-Throughput Drug Screening Technology, College of Health Science and Engineering, Hubei University, Wuhan, China
| | - Hanyang Hu
- Department of Histology and Embryology, School of Basic Medical Sciences, Wuhan University, Wuhan, 430071, China
| | - Jinjin Zhao
- The First Hospital of Changsha, Changsha, 410005, China; The Affiliated Changsha Hospital of Xiangya School of Medicine, Central South University, Changsha, 410008, China
| | - Yun Zhou
- The First Hospital of Changsha, Changsha, 410005, China; The Affiliated Changsha Hospital of Xiangya School of Medicine, Central South University, Changsha, 410008, China
| | - Dongbo Wang
- The First Hospital of Changsha, Changsha, 410005, China; The Affiliated Changsha Hospital of Xiangya School of Medicine, Central South University, Changsha, 410008, China.
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26
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Kale DS, Karande GS, Datkhile KD. Diabetic Foot Ulcer in India: Aetiological Trends and Bacterial Diversity. Indian J Endocrinol Metab 2023; 27:107-114. [PMID: 37292074 PMCID: PMC10245308 DOI: 10.4103/ijem.ijem_458_22] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/19/2022] [Revised: 03/28/2023] [Accepted: 04/02/2023] [Indexed: 06/10/2023] Open
Abstract
Diabetes is one of the most prevalent epidemic metabolic disorders, responsible for a significant amount of physical, psychological and economic loss in human society. Diabetic foot ulcer (DFU) is one of the extreme pathophysiological consequences of diabetes. Bacterial infection is the most important cause of chronic DFU. Bacterial species or their biofilms show multidrug resistance, which complicates DFU and consequently leads to amputation of the infected part. Since the Indian population comprises diverse ethnic and cultural groups, this could influence the aetiology of diabetic foot infections and bacterial diversity. We reviewed 56 articles published from 2005 to 2022 on the microbiology of DFU and extracted the data on study location, number of patients analysed in the study, pathophysiological complications, age of the patients, sex of the patient, type of bacteria, type of infection (mono or polymicrobial), predominant bacteria (Gram-positive or Gram-negative), predominant isolates and multiple drug resistance (tested or not). We analysed data and described aetiological trends in diabetic foot infections and bacterial diversity. The study revealed that Gram-negative bacteria are predominant as compared to Gram-positive bacteria in individuals with diabetes with DFU in India. Escherichia coli, Pseudomonas aeruginosa, Klebsiella sp. and Proteus sp. were the most predominant Gram-negative bacteria, while Staphylococcus aureus and Enterococcus sp. were the major Gram-positive bacteria in DFU. We discuss bacterial infections in DFU in the context of bacterial diversity, sampling methods, demography and aetiology.
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Affiliation(s)
- Dipak S. Kale
- Department of Microbiology, Krishna Institute of Medical Sciences, Karad, Satara, Maharashtra, India
| | - Geeta S. Karande
- Department of Microbiology, Krishna Institute of Medical Sciences, Karad, Satara, Maharashtra, India
| | - Kailas D. Datkhile
- Department of Molecular Biology and Genetics, Krishna Institute of Medical Sciences, Karad, Satara, Maharashtra, India
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27
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Tanwar AS, Shruptha P, Paul B, Murali TS, Brand A, Satyamoorthy K. How Can Omics Inform Diabetic Foot Ulcer Clinical Management? A Whole Genome Comparison of Four Clinical Strains of Staphylococcus aureus. OMICS : A JOURNAL OF INTEGRATIVE BIOLOGY 2023; 27:51-61. [PMID: 36753700 DOI: 10.1089/omi.2022.0184] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 02/10/2023]
Abstract
Foot ulcers and associated infections significantly contribute to morbidity and mortality in diabetes. While diverse pathogens are found in the diabetes-related infected ulcers, Staphylococcus aureus remains one of the most virulent and widely prevalent pathogens. The high prevalence of S. aureus in chronic wound infections, especially in clinical settings, is attributed to its ability to evolve and acquire resistance against common antibiotics and to elicit an array of virulence factors. In this study, whole genome comparison of four strains of S. aureus (MUF168, MUF256, MUM270, and MUM475) isolated from diabetic foot ulcer (DFU) infections showing varying resistance patterns was carried out to study the genomic similarity, antibiotic resistance profiling, associated virulence factors, and sequence variations in drug targets. The comparative genome analysis showed strains MUM475 and MUM270 to be highly resistant, MUF256 with moderate levels of resistance, and MUF168 to be the least resistant. Strain MUF256 and MUM475 harbored more virulence factors compared with other two strains. Deleterious sequence variants were observed suggesting potential role in altering drug targets and drug efficacy. This comparative whole genome study offers new molecular insights that may potentially inform evidence-based diagnosis and treatment of DFUs in the clinic.
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Affiliation(s)
- Ankit Singh Tanwar
- Department of Public Health Genomics, Manipal School of Life Sciences, Manipal Academy of Higher Education, Manipal, India.,United Nations University-Maastricht Economic and Social Research Institute on Innovation and Technology (UNU-MERIT), Maastricht, The Netherlands
| | - Padival Shruptha
- Department of Cell and Molecular Biology, Manipal School of Life Sciences, Manipal Academy of Higher Education, Manipal, India
| | - Bobby Paul
- Department of Bioinformatics, and Manipal School of Life Sciences, Manipal Academy of Higher Education, Manipal, India
| | - Thokur Sreepathy Murali
- Department of Biotechnology, Manipal School of Life Sciences, Manipal Academy of Higher Education, Manipal, India
| | - Angela Brand
- Department of Public Health Genomics, Manipal School of Life Sciences, Manipal Academy of Higher Education, Manipal, India.,United Nations University-Maastricht Economic and Social Research Institute on Innovation and Technology (UNU-MERIT), Maastricht, The Netherlands.,Faculty of Health, Medicine and Life Sciences, Maastricht University, Maastricht, The Netherlands
| | - Kapaettu Satyamoorthy
- Department of Cell and Molecular Biology, Manipal School of Life Sciences, Manipal Academy of Higher Education, Manipal, India
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M S, Mulki SS, Shenoy S, Dhanashree B, M C, Bhat G. Heterogeneous Vancomycin Intermediate Staphylococcus aureus Infections in Diabetic and Non-Diabetic Patients - A Hospital-Based Comparative Study. Infect Drug Resist 2023; 16:9-17. [PMID: 36636375 PMCID: PMC9830051 DOI: 10.2147/idr.s393415] [Citation(s) in RCA: 4] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/19/2022] [Accepted: 12/23/2022] [Indexed: 01/06/2023] Open
Abstract
Purpose To study the infections caused by methicillin resistant Staphylococcus aureus (MRSA) with emphasis on heterogeneous vancomycin intermediate S. aureus (hVISA) in diabetic and non-diabetic patients and their comparison. Patients and Methods S. aureus strains isolated from diabetic and non-diabetic patients admitted in four tertiary care hospitals in Coastal Karnataka, South India, were tested for methicillin resistance and included in the present study. Demographic and clinical data of the patients were collected using structured proforma. Antimicrobial susceptibility testing was done using the Kirby-Bauer disc diffusion method, and MLSB phenotypes were identified using the D-test. The minimum inhibitory concentration (MIC) of vancomycin was determined using agar dilution. MRSA isolates were tested for hVISA using vancomycin screen agar and population analysis profile - area under the curve (PAP-AUC) test. Statistical analysis of the results was done using the chi-square test. SPSS version 29.0 was used for this purpose. Results Out of 665 strains of S. aureus isolated, 220 (33.1%) were MRSA. Of these 220 MRSA strains, 122 (55.5%) and 98 (44.5%) were isolated from diabetic and non-diabetic patients, respectively. There was no significant difference in the antimicrobial resistance patterns of MRSA strains isolated from diabetic and non-diabetic patients. Foot infections and osteomyelitis caused by MRSA were significantly more among diabetic patients. Out of 220 strains of MRSA, 14 (6.4%) were hVISA. The rates of hVISA among MRSA isolated from diabetic and non-diabetic were 9.0% and 3.1%, respectively. This difference was statistically not significant. Conclusion The rate of hVISA among all MRSA isolates was 6.4%. The risk of hVISA infection was three times more in diabetic patients. The results emphasize the importance of the detection of hVISA among MRSA isolates especially from diabetic patients.
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Affiliation(s)
- Sreejisha M
- Department of Microbiology, Kasturba Medical College, Mangalore, Manipal Academy of Higher Education (MAHE), Manipal, Karnataka, 575001, India
| | - Shalini Shenoy Mulki
- Department of Microbiology, Kasturba Medical College, Mangalore, Manipal Academy of Higher Education (MAHE), Manipal, Karnataka, 575001, India
| | - Suchitra Shenoy
- Department of Microbiology, Kasturba Medical College, Mangalore, Manipal Academy of Higher Education (MAHE), Manipal, Karnataka, 575001, India
| | - Biranthabail Dhanashree
- Department of Microbiology, Kasturba Medical College, Mangalore, Manipal Academy of Higher Education (MAHE), Manipal, Karnataka, 575001, India
| | - Chakrapani M
- Department of Medicine, Kasturba Medical College, Mangalore, Manipal Academy of Higher Education (MAHE), Manipal, Karnataka, 575001, India
| | - Gopalakrishna Bhat
- Department of Microbiology, Kasturba Medical College, Mangalore, Manipal Academy of Higher Education (MAHE), Manipal, Karnataka, 575001, India,Correspondence: Gopalakrishna Bhat, Department of Microbiology, Kasturba Medical College, Mangalore, Manipal Academy of Higher Education (MAHE), Manipal, Karnataka, India, Tel +91 9480424729, Email
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Sun MC, Chen YF, Liu D, Xu XL, You YC, Lu W, Shi YJ, Ren MY, Fan YB, Du YZ, Tao XH. Effective decolonization strategy for mupirocin-resistant Staphylococcus aureus by TPGS-modified mupirocin-silver complex. Mater Today Bio 2023; 18:100534. [PMID: 36686036 PMCID: PMC9850068 DOI: 10.1016/j.mtbio.2022.100534] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/21/2022] [Revised: 12/11/2022] [Accepted: 12/26/2022] [Indexed: 01/04/2023]
Abstract
The widespread utilization of mupirocin to treat methicillin-resistant Staphylococcus aureus (MRSA)-caused infectious diseases has led to the emergence of mupirocin-resistant Staphylococcus aureus (MuRSA), posing a serious global medical threat. In order to counteract MuRSA, we develop a d-α-tocopherol polyethylene glycol 1000 succinate (TPGS) modified mupirocin and silver complex (TPGS/Mup-Ag) to combat MuRSA. The surfactivity of TPGS endows Mup-Ag with a homogeneous and small particle size (∼16 nm), which significantly enhances bacterial internalization. Silver ions are released from the mupirocin-Ag complex (Mup-Ag) to exert a synergistic antibacterial activity with mupirocin. Results manifest that our strategy reduces the concentration of mupirocin that induces 50% bacterial death from about 1000 μmol/mL to about 16 μmol/mL. In vitro bacterial infection model suggests that TPGS/Mup-Ag can not only eliminate both intracellular and inhibit bacterial adhesion, but also living cells are not affected. Results of in vivo experiments demonstrate that TPGS/Mup-Ag can effectively inhibit the progression of skin infection and accelerate wound healing, as well as alleviate systemic inflammation in both the subcutaneous infection model and the wound infection model. Furthermore, this study may contribute to the development of therapeutic agents for antibiotic-resistant bacteria and offer ideas for silver-based bactericides.
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Affiliation(s)
- Ming-Chen Sun
- Center for Plastic & Reconstructive Surgery, Department of Dermatology, Zhejiang Provincial People's Hospital (Affiliated People's Hospital, Hangzhou Medical College), Hangzhou, 310014, China,Institute of Pharmaceutics, College of Pharmaceutical Sciences, Zhejiang University, Hangzhou, 310058, China
| | - Ying-Fang Chen
- HangZhou Xiaoshan District Skin Disease Hospital, Hangzhou, 311200, China
| | - Di Liu
- Institute of Pharmaceutics, College of Pharmaceutical Sciences, Zhejiang University, Hangzhou, 310058, China
| | - Xiao-Ling Xu
- Shulan International Medical College, Zhejiang Shuren University, Hangzhou, 310015, China
| | - Yu-Chan You
- Institute of Pharmaceutics, College of Pharmaceutical Sciences, Zhejiang University, Hangzhou, 310058, China
| | - Wei Lu
- Center for Plastic & Reconstructive Surgery, Department of Dermatology, Zhejiang Provincial People's Hospital (Affiliated People's Hospital, Hangzhou Medical College), Hangzhou, 310014, China
| | - Yun-Juan Shi
- Department of Graduate School, Bengbu Medical College, Bengbu, 233030, China
| | - Ming-Yang Ren
- Department of Graduate School, Bengbu Medical College, Bengbu, 233030, China
| | - Yi-Bin Fan
- Center for Plastic & Reconstructive Surgery, Department of Dermatology, Zhejiang Provincial People's Hospital (Affiliated People's Hospital, Hangzhou Medical College), Hangzhou, 310014, China
| | - Yong-Zhong Du
- Institute of Pharmaceutics, College of Pharmaceutical Sciences, Zhejiang University, Hangzhou, 310058, China,Corresponding author. Institute of Pharmaceutics, College of Pharmaceutical Sciences, Zhejiang University, 866 Yu-Hang-Tang Road, Hangzhou, 310058, China.
| | - Xiao-Hua Tao
- Center for Plastic & Reconstructive Surgery, Department of Dermatology, Zhejiang Provincial People's Hospital (Affiliated People's Hospital, Hangzhou Medical College), Hangzhou, 310014, China,Corresponding author. Center for Plastic & Reconstructive Surgery, Department of Dermatology, Zhejiang Provincial People’s Hospital, 158 Shangtang Road, Hangzhou, 310014, China.
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Mamdoh H, Hassanein KM, Eltoony LF, Khalifa WA, Hamed E, Alshammari TO, Abd El-Kareem DM, El-Mokhtar MA. Clinical and Bacteriological Analyses of Biofilm-Forming Staphylococci Isolated from Diabetic Foot Ulcers. Infect Drug Resist 2023; 16:1737-1750. [PMID: 36999125 PMCID: PMC10046123 DOI: 10.2147/idr.s393724] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/30/2022] [Accepted: 01/28/2023] [Indexed: 04/01/2023] Open
Abstract
Background Diabetes mellitus is a chronic disease that is associated with increased morbidity and mortality. Unfortunately, foot ulcers and amputations due to diabetes are very common in developing countries. The purpose of this study was to characterize the clinical presentation of diabetic foot ulcer (DFU) infections, isolate the causative agent, and analyze the biofilm formation and distribution of biofilm-related genes among isolated Staphylococci. Material and Methods The study included 100 diabetic patients suffering from DFUs attending Assiut University Hospital. Swabs were collected and antimicrobial susceptibility testing of the isolates was performed. Biofilm formation was tested phenotypically among staphylococcal isolates and the frequency of different biofilm genes was analyzed by PCR. Clinical presentations of diabetic foot ulcers were correlated with bacterial genetic characteristics. Spa types were determined using DNA Gear-a software. Results Microbiological analysis showed that 94/100 of the DFUs were positive for bacterial growth. The majority of infections were polymicrobial (54%, n=54/100). Staphylococci were the most commonly detected organisms, of which S. aureus represented 37.5% (n=24/64), S. haemolyticus 23.4% (n=15/64), S. epidermidis 34.3% (n=22/64) and other CNS 4.7% (n=3/64). Interestingly, co-infection with more than one species of Staphylococci was observed in 17.1% (n=11/64) of samples. A high level of antibiotic resistance was observed, where 78.1% (n=50/64) of Staphylococci spp were multidrug-resistant (MDR). Phenotypic detection showed that all isolated Staphylococci were biofilm-formers with different grades. Analysis of biofilm-forming genes among Staphylococci showed that the most predominant genes were icaD, spa, and bap. Isolates with a higher number of biofilm-related genes were associated with strong biofilm formation. Sequencing of the spa gene in S. aureus showed that our isolates represent a collection of 17 different spa types. Conclusion The majority of DFUs in our hospital are polymicrobial. Staphylococci other than S.aureus are major contributors to infected DFUs. MDR and biofilm formation are marked among isolates, which is paralleled by the presence of different categories of virulence-related genes. All severely infected wounds were associated with either strong or intermediate biofilm formers. The severity of DFU is directly related to the number of biofilm genes.
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Affiliation(s)
- Hend Mamdoh
- Department of Microbiology and Immunology, Faculty of Pharmacy, Sphinx University, New Assiut, Egypt
| | - Khaled M Hassanein
- Department of Medical Microbiology and Immunology, Faculty of Medicine, Assiut University, Assiut, Egypt
| | - Lobna Farag Eltoony
- Department of Internal Medicine, Faculty of Medicine, Assiut University, Assiut, Egypt
| | - Walaa A Khalifa
- Department of Internal Medicine, Faculty of Medicine, Assiut University, Assiut, Egypt
| | - Entsar Hamed
- Department of Medical Microbiology and Immunology, Faculty of Medicine, Assiut University, Assiut, Egypt
| | | | - Doaa M Abd El-Kareem
- Department of Clinical Pathology, Faculty of Medicine Assiut University, Assiut, Egypt
| | - Mohamed A El-Mokhtar
- Department of Medical Microbiology and Immunology, Faculty of Medicine, Assiut University, Assiut, Egypt
- Correspondence: Mohamed A El-Mokhtar, Department of Medical Microbiology and Immunology, Faculty of Medicine, Assiut University, Assiut, Egypt, Email
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Yang L, Rong GC, Wu QN. Diabetic foot ulcer: Challenges and future. World J Diabetes 2022; 13:1014-1034. [PMID: 36578870 PMCID: PMC9791573 DOI: 10.4239/wjd.v13.i12.1014] [Citation(s) in RCA: 26] [Impact Index Per Article: 8.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/19/2022] [Revised: 10/07/2022] [Accepted: 11/28/2022] [Indexed: 12/15/2022] Open
Abstract
Diabetic foot ulcers (DFUs) have become one of the important causes of mortality and morbidity in patients with diabetes, and they are also a common cause of hospitalization, which places a heavy burden on patients and society. The prevention and treatment of DFUs requires multidisciplinary management. By controlling various risk factors, such as blood glucose levels, blood pressure, lipid levels and smoking cessation, local management of DFUs should be strengthened, such as debridement, dressing, revascularization, stem cell decompression and oxygen therapy. If necessary, systemic anti-infection treatment should be administered. We reviewed the progress in the clinical practice of treating DFUs in recent years, such as revascularization, wound repair, offloading, stem cell transplantation, and anti-infection treatment. We also summarized and prospectively analyzed some new technologies and measurements used in the treatment of DFUs and noted the future challenges and directions for the development of DFU treatments.
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Affiliation(s)
- Li Yang
- Department of Endocrinology, Dazu Hospital of Chongqing Medical University, The People's Hospital of Dazu, Chongqing 402360, China
| | - Gui-Chuan Rong
- Department of Gynaecology, Dazu Hospital of Chongqing Medical University, The People's Hospital of Dazu, Chongqing 402360, China
| | - Qi-Nan Wu
- Department of Endocrinology, Dazu Hospital of Chongqing Medical University, The People's Hospital of Dazu, Chongqing 402360, China
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Phenotypic and Genotypic Virulence Characterisation of Staphylococcus pettenkoferi Strains Isolated from Human Bloodstream and Diabetic Foot Infections. Int J Mol Sci 2022; 23:ijms232415476. [PMID: 36555117 PMCID: PMC9778964 DOI: 10.3390/ijms232415476] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/25/2022] [Revised: 11/30/2022] [Accepted: 12/02/2022] [Indexed: 12/12/2022] Open
Abstract
Staphylococcus pettenkoferi is a recently described coagulase-negative Staphylococcus identified in human diseases, especially in infections of foot ulcers in patients living with diabetes mellitus. To date, its pathogenicity remains underexplored. In this study, whole-genome analysis was performed on a collection of 29 S. pettenkoferi clinical strains isolated from bloodstream and diabetic foot infections with regard to their phylogenetic relationships and comprehensive analysis of their resistome and virulome. Their virulence was explored by their ability to form biofilm, their growth kinetics and in an in vivo zebrafish embryo infection model. Our results identified two distinct clades (I and II) and two subclades (I-a and I-b) with notable genomic differences. All strains had a slow bacterial growth. Three profiles of biofilm formation were noted, with 89.7% of isolates able to produce biofilm and harbouring a high content of biofilm-encoding genes. Two virulence profiles were also observed in the zebrafish model irrespective of the strains' origin or biofilm profile. Therefore, this study brings new insights in S. pettenkoferi pathogenicity.
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Sohail MU, Mashood F, Oberbach A, Chennakkandathil S, Schmidt F. The role of pathogens in diabetes pathogenesis and the potential of immunoproteomics as a diagnostic and prognostic tool. Front Microbiol 2022; 13:1042362. [PMID: 36483212 PMCID: PMC9724628 DOI: 10.3389/fmicb.2022.1042362] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/12/2022] [Accepted: 10/26/2022] [Indexed: 09/11/2024] Open
Abstract
Diabetes mellitus (DM) is a group of metabolic diseases marked by hyperglycemia, which increases the risk of systemic infections. DM patients are at greater risk of hospitalization and mortality from bacterial, viral, and fungal infections. Poor glycemic control can result in skin, blood, bone, urinary, gastrointestinal, and respiratory tract infections and recurrent infections. Therefore, the evidence that infections play a critical role in DM progression and the hazard ratio for a person with DM dying from any infection is higher. Early diagnosis and better glycemic control can help prevent infections and improve treatment outcomes. Perhaps, half (49.7%) of the people living with DM are undiagnosed, resulting in a higher frequency of infections induced by the hyperglycemic milieu that favors immune dysfunction. Novel diagnostic and therapeutic markers for glycemic control and infection prevention are desirable. High-throughput blood-based immunoassays that screen infections and hyperglycemia are required to guide timely interventions and efficiently monitor treatment responses. The present review aims to collect information on the most common infections associated with DM, their origin, pathogenesis, and the potential of immunoproteomics assays in the early diagnosis of the infections. While infections are common in DM, their role in glycemic control and disease pathogenesis is poorly described. Nevertheless, more research is required to identify novel diagnostic and prognostic markers to understand DM pathogenesis and management of infections. Precise monitoring of diabetic infections by immunoproteomics may provide novel insights into disease pathogenesis and healthy prognosis.
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Affiliation(s)
| | | | - Andreas Oberbach
- Experimental Cardiac Surgery LMU Munich, Department of Cardiac Surgery, Ludwig Maximillian University of Munich, Munich, Germany
| | | | - Frank Schmidt
- Proteomics Core, Weill Cornell Medicine, Doha, Qatar
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Govindasamy GA, S. M. N. Mydin RB, Harun NH, Effendy WNFWE, Sreekantan S. Giant milkweed plant-based copper oxide nanoparticles for wound dressing application: physicochemical, bactericidal and cytocompatibility profiles. CHEMICAL PAPERS 2022. [DOI: 10.1007/s11696-022-02513-5] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 11/03/2022]
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El-Shaer H, Elwakil BH, Bakr BA, Eldrieny AM, El-Khatib M, Chong KP, Abo Gazia AA. Physiotherapeutic Protocol and ZnO Nanoparticles: A Combined Novel Treatment Program against Bacterial Pyomyositis. BIOLOGY 2022; 11:1393. [PMID: 36290298 PMCID: PMC9598154 DOI: 10.3390/biology11101393] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 08/30/2022] [Revised: 09/13/2022] [Accepted: 09/14/2022] [Indexed: 11/19/2022]
Abstract
Myositis tropicans or pyomyositis is a muscle inflammation resulting from a bacterial infection of skeletal muscle (commonly caused by Staphylococcus aureus) that usually leads to hematogenous muscle seeding. The present study was designed to estimate the role of ZnO-NPs and a physiotherapeutic program in the management of induced biceps femoris atrophy in rats through histological, biochemical, and radiological examinations at different time intervals. At the beginning, several bacterial strains were evaluated through a proteolytic enzyme activity assay and the highest activity was recorded with the Staphylococcus aureus strain. ZnO-NPs were synthesized with the arc discharge method with an average size of 19.4 nm. The antibacterial activity of ZnO-NPs was investigated and it was revealed that the prepared ZnO-NPs showed a minimum inhibitory concentration of 8 µg/mL against the tested bacterium. The cytotoxicity of the prepared ZnO-NPs was tested in C2C12 myoblast cells, and it was elaborated that CC50 was 344.16 µg/mL. Biceps femoris pyomyositis was induced with a potent strain (Staphylococcus aureus); then, a physiotherapeutic program combined with the prepared ZnO-NPs treatment protocol was applied and evaluated. The combined program claimed antibacterial properties, preventing muscle atrophy, and resulted in the most comparable value of muscle mass.
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Affiliation(s)
- Hesham El-Shaer
- Faculty of Physical Therapy, Pharos University in Alexandria, Alexandria 21500, Egypt
| | - Bassma H. Elwakil
- Faculty of Applied Health Sciences Technology, Pharos University in Alexandria, Alexandria 21500, Egypt
| | - Basant A. Bakr
- Faculty of Science, Alexandria University, Alexandria 21544, Egypt
| | - Ahmed M. Eldrieny
- Faculty of Applied Health Sciences Technology, Pharos University in Alexandria, Alexandria 21500, Egypt
| | - Mostafa El-Khatib
- Faculty of Engineering, Pharos University in Alexandria, Alexandria 21500, Egypt
| | - Khim Phin Chong
- Faculty of Science and Natural Resources, Universiti Malaysia Sabah, Jalan UMS, Kota Kinabalu 88400, Sabah, Malaysia
| | - Amr A. Abo Gazia
- Faculty of Physical Therapy, Pharos University in Alexandria, Alexandria 21500, Egypt
- Faculty of Physical Therapy, Kafr Elsheikh University, Kafr Elsheikh 33516, Egypt
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Wu S, Wu B, Liu Y, Deng S, Lei L, Zhang H. Mini Review Therapeutic Strategies Targeting for Biofilm and Bone Infections. Front Microbiol 2022; 13:936285. [PMID: 35774451 PMCID: PMC9238355 DOI: 10.3389/fmicb.2022.936285] [Citation(s) in RCA: 9] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/05/2022] [Accepted: 05/25/2022] [Indexed: 12/21/2022] Open
Abstract
Bone infection results in a complex inflammatory response and bone destruction. A broad spectrum of bacterial species has been involved for jaw osteomyelitis, hematogenous osteomyelitis, vertebral osteomyelitis or diabetes mellitus, such as Staphylococcus aureus (S. aureus), coagulase-negative Staphylococcus species, and aerobic gram-negative bacilli. S. aureus is the major pathogenic bacterium for osteomyelitis, which results in a complex inflammatory response and bone destruction. Although various antibiotics have been applied for bone infection, the emergence of drug resistance and biofilm formation significantly decrease the effectiveness of those agents. In combination with gram-positive aerobes, gram-negative aerobes and anaerobes functionally equivalent pathogroups interact synergistically, developing as pathogenic biofilms and causing recurrent infections. The adhesion of biofilms to bone promotes bone destruction and protects bacteria from antimicrobial agent stress and host immune system infiltration. Moreover, bone is characterized by low permeability and reduced blood flow, further hindering the therapeutic effect for bone infections. To minimize systemic toxicity and enhance antibacterial effectiveness, therapeutic strategies targeting on biofilm and bone infection can serve as a promising modality. Herein, we focus on biofilm and bone infection eradication with targeting therapeutic strategies. We summarize recent targeting moieties on biofilm and bone infection with peptide-, nucleic acid-, bacteriophage-, CaP- and turnover homeostasis-based strategies. The antibacterial and antibiofilm mechanisms of those therapeutic strategies include increasing antibacterial agents’ accumulation by bone specific affinity, specific recognition of phage-bacteria, inhibition biofilm formation in transcription level. As chronic inflammation induced by infection can trigger osteoclast activation and inhibit osteoblast functioning, we additionally expand the potential applications of turnover homeostasis-based therapeutic strategies on biofilm or infection related immunity homeostasis for host-bacteria. Based on this review, we expect to provide useful insights of targeting therapeutic efficacy for biofilm and bone infection eradication.
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Affiliation(s)
- Shizhou Wu
- Department of Orthopedic Surgery, West China Hospital, Sichuan University, Chengdu, China
| | - Binjie Wu
- Department of Orthopedic Surgery, West China Hospital, Sichuan University, Chengdu, China
| | - Yunjie Liu
- West China School of Public Health, Sichuan University, Chengdu, China
| | - Shu Deng
- Boston University Henry M. Goldman School of Dental Medicine, Boston, MA, United States
| | - Lei Lei
- West China Hospital of Stomatology, Sichuan University, Chengdu, China
- *Correspondence: Lei Lei,
| | - Hui Zhang
- Department of Orthopedic Surgery, West China Hospital, Sichuan University, Chengdu, China
- Hui Zhang,
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Neutralizing Staphylococcus aureus Virulence with AZD6389, a Three mAb Combination, Accelerates Closure of a Diabetic Polymicrobial Wound. mSphere 2022; 7:e0013022. [PMID: 35642538 PMCID: PMC9241520 DOI: 10.1128/msphere.00130-22] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/13/2023] Open
Abstract
Nonhealing diabetic foot ulcers (DFU), a major complication of diabetes, are associated with high morbidity and mortality despite current standard of care. Since Staphylococcus aureus is the most common pathogen isolated from nonhealing and infected DFU, we hypothesized that S. aureus virulence factors would damage tissue, promote immune evasion and alter the microbiome, leading to bacterial persistence and delayed wound healing. In a diabetic mouse polymicrobial wound model with S. aureus, Pseudomonas aeruginosa, and Streptococcus pyogenes, we report a rapid bacterial proliferation, prolonged pro-inflammatory response and large necrotic lesions unclosed for up to 40 days. Treatment with AZD6389, a three-monoclonal antibody combination targeting S. aureus alpha toxin, 4 secreted leukotoxins, and fibrinogen binding cell-surface adhesin clumping factor A resulted in full skin re-epithelization 21 days after inoculation. By neutralizing multiple virulence factors, AZD6389 effectively blocked bacterial agglutination and S. aureus-mediated cell killing, abrogated S. aureus-mediated immune evasion and targeted the bacteria for opsonophagocytic killing. Neutralizing S. aureus virulence not only facilitated S. aureus clearance in lesions, but also reduced S. pyogenes and P. aeruginosa numbers, damaging inflammatory mediators and markers for neutrophil extracellular trap formation 14 days post initiation. Collectively, our data suggest that AZD6389 holds promise as an immunotherapeutic approach against DFU complications. IMPORTANCE Diabetic foot ulcers (DFU) represent a major complication of diabetes and are associated with poor quality of life and increased morbidity and mortality despite standard of care. They have a complex pathogenesis starting with superficial skin lesions, which often progress to deeper tissue structures up to the bone and ultimately require limb amputation. The skin microbiome of diabetic patients has emerged as having an impact on DFU occurrence and chronicity. DFU are mostly polymicrobial, and the Gram-positive bacterium Staphylococcus aureus detected in more than 95% of cases. S. aureus possess a collection of virulence factors which participate in disease progression and may facilitate growth of other pathogens. Here we show in a diabetic mouse wound model that targeting some specific S. aureus virulence factors with a multimechanistic antibody combination accelerated wound closure and promoted full skin re-epithelization. This work opens promising new avenues for the treatment of DFU.
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Durand BARN, Yahiaoui Martinez A, Baud D, François P, Lavigne JP, Dunyach-Remy C. Comparative genomics analysis of two Helcococcus kunzii strains co-isolated with Staphylococcus aureus from diabetic foot ulcers. Genomics 2022; 114:110365. [PMID: 35413435 DOI: 10.1016/j.ygeno.2022.110365] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/15/2021] [Revised: 03/01/2022] [Accepted: 04/06/2022] [Indexed: 01/14/2023]
Abstract
Helcococcus kunzii is a commensal Gram-positive bacterial species recovered from the human skin microbiota and considered as an opportunistic pathogen. Although little is known about its clinical significance, its increased abundance has been reported in infected wounds, particularly in foot ulcers in persons with diabetes. This species is usually detected in mixed cultures from human specimens and frequently isolated with Staphylococcus aureus. Modulation of staphylococci virulence by H. kunzii has been shown in an infection model of Caenorhabditis elegans. The aim of this study was to compare the genomes of two H. kunzii strains isolated from foot ulcers -isolate H13 and H10 showing high or low impact on S. aureus virulence, respectively- and the H. kunzii ATCC51366 strain. Whole genome analyses revealed some differences between the two strains: length (2.06 Mb (H13) and 2.05 Mb (H10) bp), GC content (29.3% (H13) and 29.5% (H10)) and gene content (1,884 (H13) and 1,786 (H10) predicted genes). The core-proteome phylogenies within the genus characterised H. kunzii H13 and H10 as genetically similar to their ancestor. The main differences between the strains were mainly in sugar-associated transporters and various hypothetical proteins. Five targets were identified as potentially involved in S. aureus virulence modulation in both genomes: the two-component iron export system and three autoinducer-like proteins. Moreover, H13 strain harbours a prophage inserted in 1,261,110-1,295,549 (attL-attR), which is absent in H10 strain. The prophage PhiCD38_2 was previously reported for its ability to modulate secretion profile, reinforcing the autoinducer-like hypothesis. In the future, transcriptomics or metaproteomics approaches could be performed to better characterize the H13 strain and possibly identify the underlying mechanism for S. aureus virulence modulation.
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Affiliation(s)
- Benjamin A R N Durand
- Bacterial Virulence and Chronic Infections, INSERM U1047, University of Montpellier, Department of Microbiology and Hospital Hygiene, University Hospital Nîmes, 30908 Nîmes, France
| | - Alex Yahiaoui Martinez
- Department of Microbiology and Hospital Hygiene, University Hospital Nîmes, University of Montpellier, 30029 Nîmes, France
| | - Damien Baud
- Department of Infectious Diseases, Genomic Research Laboratory, Geneva University Hospitals, 1205 Geneva, Switzerland
| | - Patrice François
- Department of Infectious Diseases, Genomic Research Laboratory, Geneva University Hospitals, 1205 Geneva, Switzerland
| | - Jean-Philippe Lavigne
- Bacterial Virulence and Chronic Infections, INSERM U1047, University of Montpellier, Department of Microbiology and Hospital Hygiene, University Hospital Nîmes, 30908 Nîmes, France.
| | - Catherine Dunyach-Remy
- Bacterial Virulence and Chronic Infections, INSERM U1047, University of Montpellier, Department of Microbiology and Hospital Hygiene, University Hospital Nîmes, 30908 Nîmes, France
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Hawkins BK, Barnard M, Barber KE, Stover KR, Cretella DA, Wingler MJB, Wagner JL. Diabetic foot infections: A microbiologic review. Foot (Edinb) 2022; 51:101877. [PMID: 35468387 DOI: 10.1016/j.foot.2021.101877] [Citation(s) in RCA: 13] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/30/2020] [Accepted: 10/19/2021] [Indexed: 02/04/2023]
Abstract
UNLABELLED Diabetes mellitus continues to be an increasingly common comorbidity. Diabetic foot infections are one of the most common causes of hospitalization in this population, and account for a significant portion of increased hospitalization and healthcare expenditure. Complications, such as osteomyelitis, can necessitate the use of multiple, prolonged antibiotic courses. These courses often consist of broad-spectrum, empiric therapy determined by organisms considered to be commonly associated with these types of infections. Extended periods of broad-spectrum antibiotic regimens can contribute to antibiotic resistance and ultimately limit future treatment options. Furthermore, patient specific risk factors can impact the microbiologic diversity found in these infections. As a result, it is difficult to determine if a single empiric regimen is appropriate for all instances of diabetic foot infections. OBJECTIVES AND METHODS This review analyzes global literature relating to the culture methods, incidence, risk factors, resistance patterns, and geographic distribution of the microorganisms isolated from diabetic foot infections using the PRISMA statement for systematic review and meta-analysis reporting. RESULTS Staphylococcus aureus remains a significant pathogen, with a growing incidence of Pseudomonas aeruginosa and MDR gram-negative bacilli. CONCLUSIONS Though some individualized risk factors can be useful, local epidemiology and resistance patterns remain essential for antibiotic treatment considerations.
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Affiliation(s)
- Brandon K Hawkins
- Department of Pharmacy, University of Mississippi Medical Center, 2500 N. State St., Jackson, MS, 39216, USA.
| | - Marie Barnard
- Department of Pharmacy Administration, University of Mississippi School of Pharmacy, 1018 TCRC, University, MS, 38677, USA
| | - Katie E Barber
- Department of Pharmacy Practice, University of Mississippi School of Pharmacy, 2500 N. State St., Jackson, MS, 39216, USA
| | - Kayla R Stover
- Department of Pharmacy Practice, University of Mississippi School of Pharmacy, 2500 N. State St., Jackson, MS, 39216, USA; Department of Infectious Diseases, University of Mississippi Medical Center, 2500 N. State St., Jackson, MS, 39216, USA
| | - David A Cretella
- Department of Infectious Diseases, University of Mississippi Medical Center, 2500 N. State St., Jackson, MS, 39216, USA
| | - Mary Joyce B Wingler
- Department of Infectious Diseases, University of Mississippi Medical Center, 2500 N. State St., Jackson, MS, 39216, USA
| | - Jamie L Wagner
- Department of Pharmacy Practice, University of Mississippi School of Pharmacy, 2500 N. State St., Jackson, MS, 39216, USA
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The Chronic Wound Phageome: Phage Diversity and Associations with Wounds and Healing Outcomes. Microbiol Spectr 2022; 10:e0277721. [PMID: 35435739 PMCID: PMC9248897 DOI: 10.1128/spectrum.02777-21] [Citation(s) in RCA: 17] [Impact Index Per Article: 5.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/16/2023] Open
Abstract
Two leading impediments to chronic wound healing are polymicrobial infection and biofilm formation. Recent studies have characterized the bacterial fraction of these microbiomes and have begun to elucidate compositional correlations to healing outcomes. However, the factors that drive compositional shifts are still being uncovered. The virome may play an important role in shaping bacterial community structure and function. Previous work on the skin virome determined that it was dominated by bacteriophages, viruses that infect bacteria. To characterize the virome, we enrolled 20 chronic wound patients presenting at an outpatient wound care clinic in a microbiome survey, collecting swab samples from healthy skin and chronic wounds (diabetic, venous, arterial, or pressure) before and after a single, sharp debridement procedure. We investigated the virome using a virus-like particle enrichment procedure, shotgun metagenomic sequencing, and a k-mer-based, reference-dependent taxonomic classification method. Taxonomic composition, diversity, and associations with covariates are presented. We find that the wound virome is highly diverse, with many phages targeting known pathogens, and may influence bacterial community composition and functionality in ways that impact healing outcomes. IMPORTANCE Chronic wounds are an increasing medical burden. These wounds are known to be rich in microbial content, including both bacteria and bacterial viruses (phages). The viruses may play an important role in shaping bacterial community structure and function. We analyzed the virome and bacterial composition of 20 patients with chronic wounds. The viruses found in wounds are highly diverse compared to normal skin, unlike the bacterial composition, where diversity is decreased. These data represent an initial look at this relatively understudied component of the chronic wound microbiome and may help inform future phage-based interventions.
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Pany S, Sharma BM, Sen SK, Pal BB. Association of PVL Gene in MSSA and MRSA Strains among Diabetic Ulcer Patients from Odisha, India. INT J LOW EXTR WOUND 2022:15347346221091355. [PMID: 35379025 DOI: 10.1177/15347346221091355] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/16/2022]
Abstract
Staphylococcus aureus has emerged as an important pathogen among diabetic foot ulcers in patients with diabetes. Infections with S. aureus in diabetic ulcers need surveillance of resistant microbial profile to provide the basis for empirical therapy for the reduction of lower extremities amputation. Panton valentine leucocidin (PVL) is considered as one of the major virulence gene of S. aureus which is responsible for destruction of white blood cells and tissue necrosis. This pore forming cytotoxin gene is carried out by both methicillin-susceptible S. aureus (MSSA) and methicillin-resistant S. aureus (MRSA) strains. The present study described the prevalence of PVL gene in MSSA and MRSA strains isolated from diabetic ulcer patients treated during November, 2019 to January, 2021 from a tertiary care hospital, Odisha. Infected tissue and blood samples from these patients were collected aseptically and sub-cultured using different media and standard techniques. The isolated genomic DNA of MSSA and MRSA strains were subjected to PCR assay for the detection of PVL gene. Two hundred ten S. aureus out of 402 diabetic ulcer patients were isolated having 59.52% MSSA and 40.47% MRSA strains. Wagner's grade III and grade IV ulcers were most prevalent in these ulcer patients. The prevalence of PVL gene in MSSA strains was more in comparison to MRSA strains. Forty five resistance patterns were observed from the antibiogram profiles of S. aureus. The present study highlighted that PVL gene could not be a marker for the detection of MRSA and MSSA strains in diabetic ulcer patients.
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Affiliation(s)
- Swatishree Pany
- Microbiology Division, 29727ICMR- Regional Medical Research Centre, Bhubaneswar, Odisha, India
| | - Bayasis M Sharma
- Microbiology Division, 29727ICMR- Regional Medical Research Centre, Bhubaneswar, Odisha, India
| | - Shibani K Sen
- Kanungo Diabetes and Multispecialty Hospital, Bhubaneswar, Odisha, India
| | - Bibhuti B Pal
- Microbiology Division, 29727ICMR- Regional Medical Research Centre, Bhubaneswar, Odisha, India
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The prevalence of virulence determinants in methicillin-resistant Staphylococcus aureus isolated from different infections in hospitalized patients in Poland. Sci Rep 2022; 12:5477. [PMID: 35361858 PMCID: PMC8971418 DOI: 10.1038/s41598-022-09517-x] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/25/2021] [Accepted: 03/24/2022] [Indexed: 12/17/2022] Open
Abstract
Methicillin-resistant Staphylococcus aureus (MRSA) is responsible for hard-to-treat infections. The presence of 19 virulence genes in 120 MRSA isolates obtained from hospitalized patients and genetic relationships of these isolates were investigated. The eno (100%) and ebps (93.3%) genes encoding laminin- and elastin binding proteins, respectively, were ubiquitous. Other adhesion genes: fib (77.5%), fnbB (41.6%), bbp (40.8%), cna (30.8%) encoding proteins binding fibrinogen, fibronectin, bone sialoprotein and collagen, respectively, and map/eap (62.5%), encoding Eap, were also frequent. The etB and etD genes, encoding exfoliative toxins, were present in 15.6% and 12.5% isolates, respectively. The splA, splE and sspA, encoding serine protease were detected in 100%, 70.8% and 94.2% isolates, respectively. The tst gene, encoding toxic shock syndrome toxin-1 was found in 75% isolates. The cna, map/eap and tst genes were the most common in wound isolates and much less common in blood isolates. We identified 45 different spa types, t003 (21.7%) and t008 (18.8%) being the most common. The t003 was the most frequent among isolates from the respiratory tract (35.5%), while t008 in blood isolates (40%). Identification of virulence factors of MRSA is important for evaluation of pathogen transmission rate and disease development.
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Mudrik-Zohar H, Carasso S, Gefen T, Zalmanovich A, Katzir M, Cohen Y, Paitan Y, Geva-Zatorsky N, Chowers M. Microbiome Characterization of Infected Diabetic Foot Ulcers in Association With Clinical Outcomes: Traditional Cultures Versus Molecular Sequencing Methods. Front Cell Infect Microbiol 2022; 12:836699. [PMID: 35402307 PMCID: PMC8987016 DOI: 10.3389/fcimb.2022.836699] [Citation(s) in RCA: 18] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/15/2021] [Accepted: 03/01/2022] [Indexed: 12/19/2022] Open
Abstract
Background Infected diabetic foot ulcers (IDFU) are a major complication of diabetes mellitus. These potentially limb-threatening ulcers are challenging to treat due to impaired wound healing characterizing diabetic patients and the complex microbial environment of these ulcers. Aim To analyze the microbiome of IDFU in association with clinical outcomes. Methods Wound biopsies from IDFU were obtained from hospitalized patients and were analyzed using traditional microbiology cultures, 16S rRNA sequencing and metagenomic sequencing. Patients’ characteristics, culture-based results and sequencing data were analyzed in association with clinical outcomes. Results A total of 31 patients were enrolled. Gram-negative bacteria dominated the IDFU samples (79%, 59% and 54% of metagenomics, 16S rRNA and cultures results, respectively, p<0.001). 16S rRNA and metagenomic sequencing detected significantly more anaerobic bacteria, as compared to conventional cultures (59% and 76%, respectively vs. 26% in cultures, p=0.001). Culture-based results showed that Staphylococcus aureus was more prevalent among patients who were treated conservatively (p=0.048). In metagenomic analysis, the Bacteroides genus was more prevalent among patients who underwent amputation (p<0.001). Analysis of metagenomic-based functional data showed that antibiotic resistance genes and genes related to biofilm production and to bacterial virulent factors were more prevalent in IDFU that resulted in amputation (p<0.001). Conclusion Sequencing tools uncover the complex biodiversity of IDFU and emphasize the high prevalence of anaerobes and Gram-negative bacteria in these ulcers. Furthermore, sequencing results highlight possible associations among certain genera, species, and bacterial functional genes to clinical outcomes.
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Affiliation(s)
- Hadar Mudrik-Zohar
- Department of Internal Medicine A, Meir Medical Center, Kfar Saba, Israel
- Sackler Faculty of Medicine, Tel-Aviv University, Tel-Aviv, Israel
- *Correspondence: Naama Geva-Zatorsky, ; Hadar Mudrik-Zohar,
| | - Shaqed Carasso
- Rappaport Technion Integrated Cancer Center (TICC), Department of Cell Biology and Cancer Science, Rappaport Faculty of Medicine, The Technion – Israel Institute of Technology, Haifa, Israel
| | - Tal Gefen
- Rappaport Technion Integrated Cancer Center (TICC), Department of Cell Biology and Cancer Science, Rappaport Faculty of Medicine, The Technion – Israel Institute of Technology, Haifa, Israel
| | - Anat Zalmanovich
- Sackler Faculty of Medicine, Tel-Aviv University, Tel-Aviv, Israel
- Infectious Diseases Unit, Meir Medical Center, Kfar Saba, Israel
| | - Michal Katzir
- Sackler Faculty of Medicine, Tel-Aviv University, Tel-Aviv, Israel
- Infectious Diseases Unit, Meir Medical Center, Kfar Saba, Israel
| | - Yael Cohen
- Department of Orthopedics B, Meir Medical Center, Kfar Saba, Israel
| | - Yossi Paitan
- Sackler Faculty of Medicine, Tel-Aviv University, Tel-Aviv, Israel
- Clinical Microbiology Laboratory, Meir Medical Center, Kfar Saba, Israel
| | - Naama Geva-Zatorsky
- Rappaport Technion Integrated Cancer Center (TICC), Department of Cell Biology and Cancer Science, Rappaport Faculty of Medicine, The Technion – Israel Institute of Technology, Haifa, Israel
- Canadian Institute for Advanced Research (CIFAR), Toronto, ON, Canada
- *Correspondence: Naama Geva-Zatorsky, ; Hadar Mudrik-Zohar,
| | - Michal Chowers
- Sackler Faculty of Medicine, Tel-Aviv University, Tel-Aviv, Israel
- Infectious Diseases Unit, Meir Medical Center, Kfar Saba, Israel
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Cordero M, García-Fernández J, Acosta IC, Yepes A, Avendano-Ortiz J, Lisowski C, Oesterreicht B, Ohlsen K, Lopez-Collazo E, Förstner KU, Eulalio A, Lopez D. The induction of natural competence adapts staphylococcal metabolism to infection. Nat Commun 2022; 13:1525. [PMID: 35314690 PMCID: PMC8938553 DOI: 10.1038/s41467-022-29206-7] [Citation(s) in RCA: 19] [Impact Index Per Article: 6.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/01/2020] [Accepted: 03/03/2022] [Indexed: 11/26/2022] Open
Abstract
A central question concerning natural competence is why orthologs of competence genes are conserved in non-competent bacterial species, suggesting they have a role other than in transformation. Here we show that competence induction in the human pathogen Staphylococcus aureus occurs in response to ROS and host defenses that compromise bacterial respiration during infection. Bacteria cope with reduced respiration by obtaining energy through fermentation instead. Since fermentation is energetically less efficient than respiration, the energy supply must be assured by increasing the glycolytic flux. The induction of natural competence increases the rate of glycolysis in bacteria that are unable to respire via upregulation of DNA- and glucose-uptake systems. A competent-defective mutant showed no such increase in glycolysis, which negatively affects its survival in both mouse and Galleria infection models. Natural competence foster genetic variability and provides S. aureus with additional nutritional and metabolic possibilities, allowing it to proliferate during infection.
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Affiliation(s)
- Mar Cordero
- National Centre for Biotechnology, Spanish National Research Council (CNB-CSIC), 28049, Madrid, Spain
| | - Julia García-Fernández
- National Centre for Biotechnology, Spanish National Research Council (CNB-CSIC), 28049, Madrid, Spain
| | - Ivan C Acosta
- National Centre for Biotechnology, Spanish National Research Council (CNB-CSIC), 28049, Madrid, Spain
| | - Ana Yepes
- Research Centre for Infectious Diseases (ZINF), University of Würzburg, 97080, Würzburg, Germany
- Institute for Molecular Infection Biology (IMIB), University of Würzburg, 97080, Würzburg, Germany
| | - Jose Avendano-Ortiz
- The Innate Immune Response and Tumor Immunology Group, IdiPaz La Paz University Hospital, 28046, Madrid, Spain
| | - Clivia Lisowski
- Institute for Molecular Infection Biology (IMIB), University of Würzburg, 97080, Würzburg, Germany
| | - Babett Oesterreicht
- Research Centre for Infectious Diseases (ZINF), University of Würzburg, 97080, Würzburg, Germany
- Institute for Molecular Infection Biology (IMIB), University of Würzburg, 97080, Würzburg, Germany
| | - Knut Ohlsen
- Research Centre for Infectious Diseases (ZINF), University of Würzburg, 97080, Würzburg, Germany
- Institute for Molecular Infection Biology (IMIB), University of Würzburg, 97080, Würzburg, Germany
| | - Eduardo Lopez-Collazo
- The Innate Immune Response and Tumor Immunology Group, IdiPaz La Paz University Hospital, 28046, Madrid, Spain
- CIBER of Respiratory Diseases (CIBERES), Madrid, Spain
| | - Konrad U Förstner
- Research Centre for Infectious Diseases (ZINF), University of Würzburg, 97080, Würzburg, Germany
- Institute for Molecular Infection Biology (IMIB), University of Würzburg, 97080, Würzburg, Germany
- Information Centre for Life Science (ZBMED), 50931, Cologne, Germany
- TH Köln - University of Applied Sciences, 50578, Cologne, Germany
| | - Ana Eulalio
- Institute for Molecular Infection Biology (IMIB), University of Würzburg, 97080, Würzburg, Germany
- Center for Neuroscience and Cell Biology (CNC), University of Coimbra, 3004-504, Coimbra, Portugal
- Institute of Biomedicine (iBiMED), Department of Medical Sciences, University of Aveiro, 3810-193, Aveiro, Portugal
| | - Daniel Lopez
- National Centre for Biotechnology, Spanish National Research Council (CNB-CSIC), 28049, Madrid, Spain.
- Research Centre for Infectious Diseases (ZINF), University of Würzburg, 97080, Würzburg, Germany.
- Institute for Molecular Infection Biology (IMIB), University of Würzburg, 97080, Würzburg, Germany.
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von Köckritz-Blickwede M, Winstel V. Molecular Prerequisites for Neutrophil Extracellular Trap Formation and Evasion Mechanisms of Staphylococcus aureus. Front Immunol 2022; 13:836278. [PMID: 35237275 PMCID: PMC8884242 DOI: 10.3389/fimmu.2022.836278] [Citation(s) in RCA: 24] [Impact Index Per Article: 8.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/15/2021] [Accepted: 01/19/2022] [Indexed: 12/15/2022] Open
Abstract
NETosis is a multi-facetted cellular process that promotes the formation of neutrophil extracellular traps (NETs). NETs as web-like structures consist of DNA fibers armed with granular proteins, histones, and microbicidal peptides, thereby exhibiting pathogen-immobilizing and antimicrobial attributes that maximize innate immune defenses against invading microbes. However, clinically relevant pathogens often tolerate entrapment and even take advantage of the remnants of NETs to cause persistent infections in mammalian hosts. Here, we briefly summarize how Staphylococcus aureus, a high-priority pathogen and causative agent of fatal diseases in humans as well as animals, catalyzes and concurrently exploits NETs during pathogenesis and recurrent infections. Specifically, we focus on toxigenic and immunomodulatory effector molecules produced by staphylococci that prime NET formation, and further highlight the molecular and underlying principles of suicidal NETosis compared to vital NET-formation by viable neutrophils in response to these stimuli. We also discuss the inflammatory potential of NET-controlled microenvironments, as excessive expulsion of NETs from activated neutrophils provokes local tissue injury and may therefore amplify staphylococcal disease severity in hospitalized or chronically ill patients. Combined with an overview of adaptation and counteracting strategies evolved by S. aureus to impede NET-mediated killing, these insights may stimulate biomedical research activities to uncover novel aspects of NET biology at the host-microbe interface.
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Affiliation(s)
- Maren von Köckritz-Blickwede
- Department of Biochemistry, University of Veterinary Medicine Hannover, Hannover, Germany
- Research Center for Emerging Infections and Zoonoses (RIZ), University of Veterinary Medicine Hannover, Hannover, Germany
| | - Volker Winstel
- Research Group Pathogenesis of Bacterial Infections, TWINCORE, Centre for Experimental and Clinical Infection Research, a joint venture between the Hannover Medical School and the Helmholtz Centre for Infection Research, Hannover, Germany
- Institute of Medical Microbiology and Hospital Epidemiology, Hannover Medical School, Hannover, Germany
- *Correspondence: Volker Winstel,
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Youssef CRB, Kadry AA, Mohammed El-Ganiny A. The alarming coincidence of toxin genes with staphylococcal cassette Chromosome mec (SCCmec) in clinical MRSA isolates. Saudi J Biol Sci 2022. [DOI: 10.1016/j.sjbs.2022.02.026] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/19/2022] Open
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Investigating Pathogenicity and Virulence of Staphylococcus pettenkoferi: An Emerging Pathogen. Int J Mol Sci 2021; 22:ijms222413614. [PMID: 34948410 PMCID: PMC8704685 DOI: 10.3390/ijms222413614] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/16/2021] [Revised: 12/14/2021] [Accepted: 12/16/2021] [Indexed: 01/22/2023] Open
Abstract
Staphylococcus pettenkoferi is a coagulase-negative Staphylococcus identified in 2002 that has been implicated in human diseases as an opportunistic pathogenic bacterium. Its multiresistant character is becoming a major health problem, yet the pathogenicity of S. pettenkoferi is poorly characterized. In this study, the pathogenicity of a S. pettenkoferi clinical isolate from diabetic foot osteomyelitis was compared with a Staphylococcus aureus strain in various in vitro and in vivo experiments. Growth kinetics were compared against S. aureus, and bacteria survival was assessed in the RAW 264.7 murine macrophage cell line, the THP-1 human leukemia monocytic cell line, and the HaCaT human keratinocyte cell line. Ex vivo analysis was performed in whole blood survival assays and in vivo assays via the infection model of zebrafish embryos. Moreover, whole-genome analysis was performed. Our results show that S. pettenkoferi was able to survive in human blood, human keratinocytes, murine macrophages, and human macrophages. S. pettenkoferi demonstrated its virulence by causing substantial embryo mortality in the zebrafish model. Genomic analysis revealed virulence factors such as biofilm-encoding genes (e.g., icaABCD; rsbUVW) and regulator-encoding genes (e.g., agr, mgrA, sarA, saeS) well characterized in S. aureus. This study thus advances the knowledge of this under-investigated pathogen and validates the zebrafish infection model for this bacterium.
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Evaluation of the Use of Antibiofilmogram Technology in the Clinical Evolution of Foot Ulcers Infected by Staphylococcus aureus in Persons Living with Diabetes: A Pilot Study. J Clin Med 2021; 10:jcm10245928. [PMID: 34945223 PMCID: PMC8705769 DOI: 10.3390/jcm10245928] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/10/2021] [Revised: 12/08/2021] [Accepted: 12/15/2021] [Indexed: 01/22/2023] Open
Abstract
Infected diabetic foot ulcers (DFUs) represent a serious threat to public health because of their frequency and the severity of their consequences. DFUs are frequently infected by bacteria in biofilms, obstructing antibiotic action. Antibiofilmogram was developed to assess the impact of antibiotics to inhibit biofilm formation. This pilot study aimed to determine the benefits of this technology in predicting antibiotic activity on the outcome of 28 patients with Grade 2 DFUs that were infected by a monomicrobial Staphylococcus aureus. Patients with diabetes were followed during the antibiotic treatment (day 14) and the follow-up period of the study (day 45). The contribution of Antibiofilmogram was compared between patients with non-concordant results (n = 13) between antibiogram and Antibiofilmogram versus concordant results (n = 15). The clinical improvement of wounds (80.0% vs. 38.5%, p = 0.0245) and the absence of exudates (0% vs. 33.3%, p = 0.0282) were observed in concordant vs. discordant groups. This pilot study provides promising results for the interest of Antibiofilmogram in the prescription of antibiotics to prevent biofilm formation in infected DFUs.
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Fayolle M, Morsli M, Gelis A, Chateauraynaud M, Yahiaoui-Martinez A, Sotto A, Lavigne JP, Dunyach-Remy C. The Persistence of Staphylococcus aureus in Pressure Ulcers: A Colonising Role. Genes (Basel) 2021; 12:1883. [PMID: 34946833 PMCID: PMC8701790 DOI: 10.3390/genes12121883] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/24/2021] [Revised: 11/19/2021] [Accepted: 11/22/2021] [Indexed: 11/17/2022] Open
Abstract
Decubitus pressure ulcers (PU) are a major complication of immobilised patients. Staphylococcus aureus is one of the most frequently detected microorganisms in PU samples; however, its persistence and role in the evolution of these wounds is unknown. In this study, we analysed S. aureus strains isolated from PU biopsies at inclusion and day 28. Eleven S. aureus (21.1%) were detected in 52 patients at inclusion. Only six PUs (11.5%) continued to harbour this bacterium at day 28. Using a whole genome sequencing approach (Miseq®, Illumina), we confirmed that these six S. aureus samples isolated at D28 were the same strain as that isolated at inclusion, with less than 83 bp difference. Phenotypical studies evaluating the growth profiles (Infinite M Mano, Tecan®) and biofilm formation (Biofilm Ring Test®) did not detect any significant difference in the fitness of the pairs of S. aureus. However, using the Caenorhabditis elegans killing assay, a clear decrease of virulence was observed between strains isolated at D28 compared with those isolated at inclusion, regardless of the clinical evolution of the PU. Moreover, all strains at inclusion were less virulent than a control S. aureus strain, i.e., NSA739. An analysis of polymicrobial communities of PU (by metabarcoding approach), in which S. aureus persisted, demonstrated no impact of Staphylococcus genus on PU evolution. Our study suggested that S. aureus presented a colonising profile on PU with no influence on wound evolution.
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Affiliation(s)
- Martin Fayolle
- Virulence Bactérienne et Infections Chroniques, INSERM U1047, Université de Montpellier, Service de Microbiologie et Hygiène Hospitalière, CHU Nîmes, 30908 Nîmes, France; (M.F.); (A.Y.-M.); (C.D.-R.)
| | - Madjid Morsli
- IRD, Microbes, Evolution, Phylogeny and Infection (MEPHI), Aix-Marseille-Université, IHU Méditerranée Infection, 13005 Marseille, France;
| | - Anthony Gelis
- Centre Mutualiste Neurologique Propara, 34090 Montpellier, France;
| | - Marion Chateauraynaud
- Virulence Bactérienne et Infections Chroniques, INSERM U1047, Université de Montpellier, 30908 Nîmes, France;
| | - Alex Yahiaoui-Martinez
- Virulence Bactérienne et Infections Chroniques, INSERM U1047, Université de Montpellier, Service de Microbiologie et Hygiène Hospitalière, CHU Nîmes, 30908 Nîmes, France; (M.F.); (A.Y.-M.); (C.D.-R.)
| | - Albert Sotto
- Virulence Bactérienne et Infections Chroniques, INSERM U1047, Université de Montpellier, Service de Maladies Infectieuses et Tropicales, CHU Nîmes, 30908 Nîmes, France;
| | - Jean-Philippe Lavigne
- Virulence Bactérienne et Infections Chroniques, INSERM U1047, Université de Montpellier, Service de Microbiologie et Hygiène Hospitalière, CHU Nîmes, 30908 Nîmes, France; (M.F.); (A.Y.-M.); (C.D.-R.)
| | - Catherine Dunyach-Remy
- Virulence Bactérienne et Infections Chroniques, INSERM U1047, Université de Montpellier, Service de Microbiologie et Hygiène Hospitalière, CHU Nîmes, 30908 Nîmes, France; (M.F.); (A.Y.-M.); (C.D.-R.)
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Párraga Solórzano PK, Shupe AC, Kehl-Fie TE. The Sensor Histidine Kinase ArlS Is Necessary for Staphylococcus aureus To Activate ArlR in Response to Nutrient Availability. J Bacteriol 2021; 203:e0042221. [PMID: 34606376 PMCID: PMC8604075 DOI: 10.1128/jb.00422-21] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/24/2021] [Accepted: 09/25/2021] [Indexed: 12/12/2022] Open
Abstract
Staphylococcus aureus is a versatile opportunistic pathogen whose success is driven by its ability to adapt to diverse environments and host-imposed stresses. Two-component signal transduction systems, such as ArlRS, often mediate these adaptations. Loss of ArlRS or the response regulator ArlR alone impairs the ability of S. aureus to respond to host-imposed manganese starvation and glucose limitation. As sensor histidine kinases and response regulators frequently work as pairs, it has been assumed that ArlS senses and activates ArlR in response to these stimuli. However, recent work suggests that the sensor histidine kinase GraS can also activate ArlR, calling the contribution of ArlS in responding to manganese and glucose availability into question. The results of current studies reveal that ArlS is necessary to activate ArlR in response to manganese sequestration by the host immune effector calprotectin and glucose limitation. Although the loss of ArlS does not completely eliminate ArlR activity, this response regulator is no longer responsive to manganese or glucose availability in the absence of its cognate histidine kinase. Despite the residual activity of ArlR in the absence of ArlS, ArlR phosphorylation by ArlS is required for S. aureus to resist calprotectin-imposed metal starvation. Cumulatively, these findings contribute to the understanding of S. aureus signal transduction in response to nutritional immunity and support the previous observation indicating that ArlRS is activated by a common signal derived from host-imposed manganese and glucose limitation. IMPORTANCE The ability of pathogens, including Staphylococcus aureus, to sense and adapt to diverse environments partially relies on two-component systems, such as ArlRS. Recent work revealed that the response regulator ArlR can be cross-activated by the sensor histidine kinase GraS, rendering the role of its cognate partner, ArlS, in response to manganese and glucose limitation uncertain. The results of this study reveal that ArlS is necessary for the activation of ArlR in response to calprotectin and glucose limitation. Although a low level of ArlR activity remains in the absence of ArlS, ArlS phosphotransfer to ArlR is required for S. aureus to overcome calprotectin-induced nutritional stress. Collectively, this study provides fundamental information to understand how ArlRS mediates staphylococcal adaptation during infection.
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Affiliation(s)
| | - Angela C. Shupe
- Department of Microbiology, University of Illinois Urbana-Champaign, Urbana, Illinois, USA
| | - Thomas E. Kehl-Fie
- Department of Microbiology, University of Illinois Urbana-Champaign, Urbana, Illinois, USA
- Carl R. Woese Institute for Genomic Biology, University of Illinois Urbana-Champaign, Urbana, Illinois, USA
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