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Jernigan DA, Hentish RD. Successful Treatment of a Patient With Chronic Bronchiectasis Using an Induced Native Phage Cocktail: A Case Report. Cureus 2025; 17:e77681. [PMID: 39834667 PMCID: PMC11744022 DOI: 10.7759/cureus.77681] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 01/19/2025] [Indexed: 01/22/2025] Open
Abstract
Bronchiectasis is a well-recognized chronic respiratory disease characterized by a productive cough and multi-microbial activation syndrome (MMAS) of various respiratory infections due to what can be the permanent dilatation of the bronchi. Bronchiectasis represents an ongoing challenge to conventional antibiotic treatment as the damaged bronchial environment remains conducive to ongoing opportunistic infections and microbial mutations, leading to multi-drug resistance. Standard treatment guidelines are designed to promptly identify and address the primary infection. Despite the strong focus on identification of the primary infection in each new episode, by combining clinical history, and high-resolution computed tomography (HRCT), a high proportion of patients remain classified as "idiopathic". Important underlying infections, such as Aspergillus and other mold infections, Pseudomonas aeruginosa, Mycobacterium, Mycoplasma, and various viruses, are frequently not identified for prolonged periods of time, and selected broad-spectrum antibiotics are often ineffective. The introduction of Induced Native Phage Therapy in 2021 and Induced Native Phage cocktails in 2024 provides a new treatment alternative that induces naturally occurring phages to eliminate specifically targeted acute and chronic mixed infections even in cases of multi-drug resistant infections as seen in chronic bronchiectasis. This article will present the successful long-term results in a case study demonstrating the speed, gentleness, and effectiveness of induced native phage cocktails in a 45-year-old male with life-long asthma resulting in multi-microbial activation syndrome in severe non-cystic fibrosis bronchiectasis for the last 20 years.
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Affiliation(s)
- David A Jernigan
- Bioregulatory Medicine, Biologix Center for Optimum Health, Franklin, USA
| | - Roman D Hentish
- Bioregulatory Medicine, Chronic Illness, Biologix Center for Optimum Health, Franklin, USA
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2
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Oliveira VDC, Soler-Comas A, Rocha AC, Silva-Lovato CH, Watanabe E, Torres A, Fernández-Barat L. The synergistic effect between phages and Ceftolozane/Tazobactam in Pseudomonas aeruginosa endotracheal tube biofilm. Emerg Microbes Infect 2024; 13:2420737. [PMID: 39530158 PMCID: PMC11571741 DOI: 10.1080/22221751.2024.2420737] [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: 05/22/2024] [Revised: 09/26/2024] [Accepted: 10/20/2024] [Indexed: 11/16/2024]
Abstract
Although an increased effectiveness has been suggested when phages and antibiotics are combined, this approach has not been tested against a mature biofilm on an endotracheal tube (ETT) surface. This study evaluated the effect of short- and long-term combined phage-antibiotic therapy in a control of a mature biofilm on an ETT surface. Pseudomonas aeruginosa strains, including susceptible and resistant clinical samples, were used to develop the ETT biofilm. Biofilm was treated with 108PFU/mL of phage_2, phage_18 or 5 μg/mL of ceftolozane/tazobactam, alone or in combination with phages. The sequential combination of the two different phages and ceftolozane/tazobactam was also tested. Biofilm viability was assessed after short (2, 4, 24 h) and long-(48, 72 h) term treatment exposure using colony forming unit measurement. For long-term exposition, a new treatment shot was added every 24 h. In the sequential combination, the phage type was switched at 24 h of treatment. Regarding the susceptible strains, the treatments had limited antibiofilm effect after 2, 4 and 24 h. After 48 and 72 h, administering phages alone had no effect on biofilm viability, indicating the emergence of phage-resistant phenotypes. Nonetheless, the combined phage-antibiotic treatment reduced the biofilm viability in about 5-log, whilst antibiotic alone reduced in about 3-log. The sequential combination of phages and antibiotic reduced the biofilm viability in about 6-log. With respect to the resistant strains, no antibiofilm activity was observed regarding the treatment arms. The combination of phages and ceftolozane/tazobactam showed a synergism strain-dependent, being more apparent in susceptible strains.
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Affiliation(s)
- Viviane de C. Oliveira
- Department of Dental Materials and Prostheses, School of Dentistry of Ribeirão Preto, University of São Paulo, São Paulo, Brazil
- Human Exposome and Infectious Diseases Network – HEID, School of Nursing of Ribeirão Preto, University of São Paulo, São Paulo, Brazil
| | - Alba Soler-Comas
- Institut d’Investigacions Biomèdiques August Pi i Sunyer – IDIBAPS, Barcelona, Spain
- Centro de Investigación Biomédica en Red de enfermedades respiratorias (Ciberes) – Hospital Clinic de Barcelona, Barcelona, Spain
- University of Barcelona, Barcelona, Spain
| | - Amanda C.S.D. Rocha
- Human Exposome and Infectious Diseases Network – HEID, School of Nursing of Ribeirão Preto, University of São Paulo, São Paulo, Brazil
| | - Cláudia H. Silva-Lovato
- Department of Dental Materials and Prostheses, School of Dentistry of Ribeirão Preto, University of São Paulo, São Paulo, Brazil
| | - Evandro Watanabe
- Human Exposome and Infectious Diseases Network – HEID, School of Nursing of Ribeirão Preto, University of São Paulo, São Paulo, Brazil
- Department of Restorative Dentistry, School of Dentistry of Ribeirão Preto, University of São Paulo, São Paulo, Brazil
| | - Antoni Torres
- Institut d’Investigacions Biomèdiques August Pi i Sunyer – IDIBAPS, Barcelona, Spain
- Centro de Investigación Biomédica en Red de enfermedades respiratorias (Ciberes) – Hospital Clinic de Barcelona, Barcelona, Spain
- University of Barcelona, Barcelona, Spain
| | - Laia Fernández-Barat
- Institut d’Investigacions Biomèdiques August Pi i Sunyer – IDIBAPS, Barcelona, Spain
- Centro de Investigación Biomédica en Red de enfermedades respiratorias (Ciberes) – Hospital Clinic de Barcelona, Barcelona, Spain
- University of Barcelona, Barcelona, Spain
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3
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Høiby N, Moser C, Ciofu O. Pseudomonas aeruginosa in the Frontline of the Greatest Challenge of Biofilm Infection-Its Tolerance to Antibiotics. Microorganisms 2024; 12:2115. [PMID: 39597505 PMCID: PMC11596597 DOI: 10.3390/microorganisms12112115] [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: 09/17/2024] [Revised: 10/17/2024] [Accepted: 10/20/2024] [Indexed: 11/29/2024] Open
Abstract
P. aeruginosa biofilms are aggregates of bacteria surrounded by a self-produced matrix which binds to some antibiotics such as aminoglycosides. P. aeruginosa biofilms are tolerant to antibiotics. The treatment of biofilm infections leads to a recurrence of symptoms after finishing antibiotic treatment, although the initial clinical response to the treatment is frequently favorable. There is a concentration gradient of oxygen and nutrients from the surface to the center of biofilms. Surface-located bacteria are multiplying and metabolizing, whereas deeper located bacteria are dormant and tolerant to most antibiotics. Colistin kills dormant bacteria, and combination therapy with colistin and antibiotics which kills multiplying bacteria is efficient in vitro. Some antibiotics such as imipenem induce additional production of the biofilm matrix and of chromosomal beta-lactamase in biofilms. Biofilms present a third Pharmacokinetic/Pharmacodynamic (PK/PD) micro-compartment (first: blood, second: tissue, third: biofilm) which must be taken into consideration when calculations try to predict the antibiotic concentrations in biofilms and thereby the probability of target attainment (PTA) for killing the biofilm. Treating biofilms with hyperbaric oxygen to wake up the dormant cells, destruction of the biofilm matrix, and the use of bacteriophage therapy in combination with antibiotics are promising possibilities which have shown proof of concept in in vitro experiments and in animal experiments.
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Affiliation(s)
- Niels Høiby
- Institute of Immunology and Microbiology, Costerton Biofilm Center, Faculty of Health Science, University of Copenhagen, DK-2200 Copenhagen, Denmark; (C.M.); (O.C.)
- Department of Clinical Microbiology, Rigshospitalet, University of Copenhagen, DK-2100 Copenhagen, Denmark
| | - Claus Moser
- Institute of Immunology and Microbiology, Costerton Biofilm Center, Faculty of Health Science, University of Copenhagen, DK-2200 Copenhagen, Denmark; (C.M.); (O.C.)
- Department of Clinical Microbiology, Rigshospitalet, University of Copenhagen, DK-2100 Copenhagen, Denmark
| | - Oana Ciofu
- Institute of Immunology and Microbiology, Costerton Biofilm Center, Faculty of Health Science, University of Copenhagen, DK-2200 Copenhagen, Denmark; (C.M.); (O.C.)
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4
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Abdelhadi AA, Elarabi NI, Ibrahim SM, Abdel-Maksoud MA, Abdelhaleem HAR, Almutairi S, Malik A, Kiani BH, Henawy AR, Halema AA. Hybrid-genome sequence analysis of Enterobacter cloacae FACU and morphological characterization: insights into a highly arsenic-resistant strain. Funct Integr Genomics 2024; 24:174. [PMID: 39320439 DOI: 10.1007/s10142-024-01441-9] [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: 06/23/2024] [Revised: 08/28/2024] [Accepted: 09/03/2024] [Indexed: 09/26/2024]
Abstract
Many organisms have adapted to survive in environments with high levels of arsenic (As), a naturally occurring metalloid with various oxidation states and a common element in human activities. These organisms employ diverse mechanisms to resist the harmful effects of arsenic compounds. Ten arsenic-resistant bacteria were isolated from contaminated wastewater in this study. The most efficient bacterial isolate able to resist 15,000 ppm Na2HAsO4·7H2O was identified using the 16S rRNA gene and whole genome analysis as Enterobacter cloacae FACU. The arsenic E. cloacae FACU biosorption capability was analyzed. To further unravel the genetic determinants of As stress resistance, the whole genome sequence of E. cloacae FACU was performed. The FACU complete genome sequence consists of one chromosome (5.7 Mb) and two plasmids, pENCL 1 and pENCL 2 (755,058 and 1155666 bp, respectively). 7152 CDSs were identified in the E. cloacae FACU genome. The genome consists of 130 genes for tRNA and 21 for rRNAs. The average G + C content was found to be 54%. Sequencing analysis annotated 58 genes related to resistance to many heavy metals, including 16 genes involved in arsenic efflux transporter and arsenic reduction (five arsRDABC genes) and 42 genes related to lead, zinc, mercury, nickel, silver, copper, cadmium and chromium in FACU. Scanning electron microscopy (SEM) confirmed the difference between the morphological responses of the As-treated FACU compared to the control strain. The study highlights the genes involved in the mechanism of As stress resistance, metabolic pathways, and potential activity of E. cloacae FACU at the genetic level.
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Affiliation(s)
- Abdelhadi A Abdelhadi
- Department of Genetics, Faculty of Agriculture, Cairo University, Giza, 12613, Egypt.
| | - Nagwa I Elarabi
- Department of Genetics, Faculty of Agriculture, Cairo University, Giza, 12613, Egypt.
| | - Saifeldeen M Ibrahim
- Biotechnology Department, Faculty of Agriculture, Al-Azhar University, Cairo, Egypt
- Bioinformatics Department, Agricultural Genetic Engineering Research Institute, ARC, Giza, Egypt
| | - Mostafa A Abdel-Maksoud
- Botany and Microbiology Department, College of Science, King Saud University, Riyadh, Saudi Arabia
| | - Heba A R Abdelhaleem
- College of Biotechnology, Misr University for Science and Technology (MUST), 6th October City, Egypt
| | - Saeedah Almutairi
- Botany and Microbiology Department, College of Science, King Saud University, Riyadh, Saudi Arabia
| | - Abdul Malik
- Department of Pharmaceutics, College of Pharmacy, King Saud University, Riyadh, Saudi Arabia
| | - Bushra Hafeez Kiani
- Department of Biology and Biotechnology, Worcester Polytechnic Institute, Worcester, Massachuesetts, 01609, USA
| | - Ahmed R Henawy
- Department of Microbiology, Faculty of Agriculture, Cairo University, Giza, 12613, Egypt
| | - Asmaa A Halema
- Department of Genetics, Faculty of Agriculture, Cairo University, Giza, 12613, Egypt
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Damar Celik D, Karaynir A, Salih Dogan H, Bozdogan B, Ozbek Celik B. Characterization and genomic analysis of PA-56 Pseudomonas phage from Istanbul, Turkey: Antibacterial and antibiofilm efficacy alone and with antibiotics. Heliyon 2024; 10:e36243. [PMID: 39263065 PMCID: PMC11387251 DOI: 10.1016/j.heliyon.2024.e36243] [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: 03/26/2024] [Revised: 08/08/2024] [Accepted: 08/13/2024] [Indexed: 09/13/2024] Open
Abstract
Phages are ubiquitous in freshwater, seawater, soil, the human body, and sewage water. They are potent biopharmaceuticals against antimicrobial-resistant bacteria and offer a promising alternative for treating infectious diseases. Also, combining phages with antibiotics enhances the antibiotics' efficacy. This study focused on two Pseudomonas aeruginosa phages isolated from lake and sewage water samples and one of them selected for further investigation. Isolated phages PA-56 and PA-18 infected 92 % and 86 % of the tested 25 clinical Pseudomonas aeruginosa strains, respectively. PA-56 with strong activity was chosen for detailed characterization, antimicrobial studies, and genome analysis. Combining PA-56 with ciprofloxacin or meropenem demonstrated phage-antibiotic synergism and increased antibiofilm efficacy. Genome analysis revealed a GC ratio of 54 % and a genome size of 42.761 bp, with no virulence or antibiotic resistance genes. Notably, PA-56 harboured the toxin-antitoxin protein, MazG. Overall, this study suggests that PA-56 holds promise for future applications in industry or medicine.
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Affiliation(s)
- Damla Damar Celik
- Istanbul University Institute of Graduate Studies in Health Sciences Department of Pharmaceutical Microbiology, 34116, Beyazıt, Istanbul, Turkey
| | - Abdulkerim Karaynir
- Recombinant DNA and Recombinant Protein Research Center (REDPROM), Aydın Adnan Menderes University, Aydın, Turkey
| | - Hanife Salih Dogan
- Recombinant DNA and Recombinant Protein Research Center (REDPROM), Aydın Adnan Menderes University, Aydın, Turkey
| | - Bulent Bozdogan
- Recombinant DNA and Recombinant Protein Research Center (REDPROM), Aydın Adnan Menderes University, Aydın, Turkey
- Medical Faculty, Department of Medical Microbiology, Aydın Adnan Menderes University, Aydın, Turkey
| | - Berna Ozbek Celik
- Department of Pharmaceutical Microbiology, Faculty of Pharmacy, Istanbul University, 34116, Beyazit, Istanbul, Turkey
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Martinet MG, Lohde M, Higazy D, Brandt C, Pletz MW, Middelboe M, Makarewicz O, Ciofu O. Diversification of Pseudomonas aeruginosa Biofilm Populations under Repeated Phage Exposures Decreases the Efficacy of the Treatment. Microorganisms 2024; 12:1880. [PMID: 39338555 PMCID: PMC11434582 DOI: 10.3390/microorganisms12091880] [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: 08/12/2024] [Revised: 09/05/2024] [Accepted: 09/10/2024] [Indexed: 09/30/2024] Open
Abstract
Phage therapy has been proposed as a therapeutic alternative to antibiotics for the treatment of chronic, biofilm-related P. aeruginosa infections. To gain a deeper insight into the complex biofilm-phage interactions, we investigated in the present study the effect of three successive exposures to lytic phages of biofilms formed by the reference strains PAO1 and PA14 as well as of two sequential clinical P. aeruginosa isolates from the sputum of a patient with cystic fibrosis (CF). The Calgary device was employed as a biofilm model and the efficacy of phage treatment was evaluated by measurements of the biomass stained with crystal violet (CV) and of the cell density of the biofilm bacterial population (CFU/mL) after each of the three phage exposures. The genetic alterations of P. aeruginosa isolates from biofilms exposed to phages were investigated by whole-genome sequencing. We show here that the anti-biofilm efficacy of the phage treatment decreased rapidly with repeated applications of lytic phages on P. aeruginosa strains with different genetic backgrounds. Although we observed the maintenance of a small subpopulation of sensitive cells after repeated phage treatments, a fast recruitment of mechanisms involved in the persistence of biofilms to the phage attack occurred, mainly by mutations causing alterations of the phage receptors. However, mutations causing phage-tolerant phenotypes such as alginate-hyperproducing mutants were also observed. In conclusion, a decreased anti-biofilm effect occurred after repeated exposure to lytic phages of P. aeruginosa biofilms due to the recruitment of different resistance and tolerance mechanisms.
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Affiliation(s)
- Mark Grevsen Martinet
- Institute of Infectious Diseases and Infection Control, Jena University Hospital, 07747 Jena, Germany; (M.G.M.); (M.L.); (C.B.); (M.W.P.); (O.M.)
| | - Mara Lohde
- Institute of Infectious Diseases and Infection Control, Jena University Hospital, 07747 Jena, Germany; (M.G.M.); (M.L.); (C.B.); (M.W.P.); (O.M.)
| | - Doaa Higazy
- Costerton Biofilm Center, Department of Immunology and Microbiology, Faculty of Health and Medical Sciences, University of Copenhagen, 2200 Copenhagen, Denmark;
| | - Christian Brandt
- Institute of Infectious Diseases and Infection Control, Jena University Hospital, 07747 Jena, Germany; (M.G.M.); (M.L.); (C.B.); (M.W.P.); (O.M.)
- Leibniz Center for Photonics in Infection Research (LPI), 07745 Jena, Germany
| | - Mathias W. Pletz
- Institute of Infectious Diseases and Infection Control, Jena University Hospital, 07747 Jena, Germany; (M.G.M.); (M.L.); (C.B.); (M.W.P.); (O.M.)
- Leibniz Center for Photonics in Infection Research (LPI), 07745 Jena, Germany
| | - Mathias Middelboe
- Marine Biological Section, Department of Biology, University of Copenhagen, 3000 Helsingør, Denmark;
- Department of Biology, University of Southern Denmark, 5230 Odense, Denmark
| | - Oliwia Makarewicz
- Institute of Infectious Diseases and Infection Control, Jena University Hospital, 07747 Jena, Germany; (M.G.M.); (M.L.); (C.B.); (M.W.P.); (O.M.)
- Leibniz Center for Photonics in Infection Research (LPI), 07745 Jena, Germany
| | - Oana Ciofu
- Costerton Biofilm Center, Department of Immunology and Microbiology, Faculty of Health and Medical Sciences, University of Copenhagen, 2200 Copenhagen, Denmark;
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Martinho I, Braz M, Duarte J, Brás A, Oliveira V, Gomes NCM, Pereira C, Almeida A. The Potential of Phage Treatment to Inactivate Planktonic and Biofilm-Forming Pseudomonas aeruginosa. Microorganisms 2024; 12:1795. [PMID: 39338470 PMCID: PMC11433742 DOI: 10.3390/microorganisms12091795] [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: 08/07/2024] [Revised: 08/18/2024] [Accepted: 08/20/2024] [Indexed: 09/30/2024] Open
Abstract
Pseudomonas aeruginosa is a common cause of hospital-acquired infections and exhibits a strong resistance to antibiotics. An alternative treatment option for bacterial infections is the use of bacteriophages (or phages). In this study, two distinct phages, VB_PaD_phPA-G (phPA-G) and VB_PaN_phPA-Intesti (phPA-Intesti), were used as single suspensions or in a phage cocktail to inactivate the planktonic cells and biofilms of P. aeruginosa. Preliminary experiments in culture medium showed that phage phPA-Intesti (reductions of 4.5-4.9 log CFU/mL) outperformed phPA-G (reductions of 0.6-2.6 log CFU/mL) and the phage cocktail (reduction of 4.2 log CFU/mL). Phage phPA-Intesti caused a maximum reduction of 5.5 log CFU/cm2 in the P. aeruginosa biofilm in urine after 4 h of incubation. The combination of phage phPA-Intesti and ciprofloxacin did not improve the efficacy of bacterial inactivation nor reduce the development of resistant mutants. However, the development of resistant bacteria was lower in the combined treatment with the phage and the antibiotic compared to treatment with the antibiotic alone. This phage lacks known toxins, virulence, antibiotic resistance, and integrase genes. Overall, the results suggest that the use of phage phPA-Intesti could be a potential approach to control urinary tract infections (UTIs), namely those caused by biofilm-producing and multidrug-resistant strains of P. aeruginosa.
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Affiliation(s)
- Inês Martinho
- Department of Biology and CESAM, University of Aveiro, Campus Universitário de Santiago, 3810-193 Aveiro, Portugal
| | - Márcia Braz
- Department of Biology and CESAM, University of Aveiro, Campus Universitário de Santiago, 3810-193 Aveiro, Portugal
| | - João Duarte
- Department of Biology and CESAM, University of Aveiro, Campus Universitário de Santiago, 3810-193 Aveiro, Portugal
| | - Ana Brás
- Department of Biology and CESAM, University of Aveiro, Campus Universitário de Santiago, 3810-193 Aveiro, Portugal
| | - Vanessa Oliveira
- Department of Biology and CESAM, University of Aveiro, Campus Universitário de Santiago, 3810-193 Aveiro, Portugal
| | - Newton C M Gomes
- Department of Biology and CESAM, University of Aveiro, Campus Universitário de Santiago, 3810-193 Aveiro, Portugal
| | - Carla Pereira
- Department of Biology and CESAM, University of Aveiro, Campus Universitário de Santiago, 3810-193 Aveiro, Portugal
| | - Adelaide Almeida
- Department of Biology and CESAM, University of Aveiro, Campus Universitário de Santiago, 3810-193 Aveiro, Portugal
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Santamaría-Corral G, Aguilera-Correa JJ, Esteban J, García-Quintanilla M. Bacteriophage Therapy on an In Vitro Wound Model and Synergistic Effects in Combination with Beta-Lactam Antibiotics. Antibiotics (Basel) 2024; 13:800. [PMID: 39334975 PMCID: PMC11428794 DOI: 10.3390/antibiotics13090800] [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: 07/20/2024] [Revised: 08/19/2024] [Accepted: 08/21/2024] [Indexed: 09/30/2024] Open
Abstract
One of the primary opportunistic pathogens that can cause a wide range of diseases is Pseudomonas aeruginosa. This microorganism can become resistant to practically every antibacterial currently in use, including beta-lactam antibiotics. Its ability to proliferate as biofilm has been linked to, among other things, the failure of antimicrobial therapies. Due to a variety of virulence factors and host immune system modifications, P. aeruginosa is one of the most significant and common bacteria that colonize wounds and burns. A novel therapeutic option for treating these multidrug-resistant (MDR) bacterial infections is the combination of antibiotics and bacteriophages. This approach has been linked to improved biofilm penetration, a decreased selection of antibiotic and bacteriophage resistance, and an enhanced antibacterial impact. Combining the F1Pa bacteriophage and beta-lactam antibiotics reduced the viability of the mature biofilm of MDR P. aeruginosa strains and suppressed bacterial growth in vitro. F1Pa critically reduced the amount of biofilm that MDR P. aeruginosa clinical strains formed in the in vitro wound model. These findings highlight the bacteriophage F1Pa's therapeutic potential as a prophylactic topical treatment against MDR pseudomonal infections in wounds and burns.
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Affiliation(s)
- Guillermo Santamaría-Corral
- Clinical Microbiology Department, IIS-Fundación Jiménez Díaz, Universidad Autónoma de Madrid, 28040 Madrid, Spain
| | - John Jairo Aguilera-Correa
- Clinical Microbiology Department, IIS-Fundación Jiménez Díaz, Universidad Autónoma de Madrid, 28040 Madrid, Spain
- CIBERINFEC-Consorcio Centro de Investigación Biomédica en Red (CIBER) de Enfermedades Infecciosas, 28029 Madrid, Spain
| | - Jaime Esteban
- Clinical Microbiology Department, IIS-Fundación Jiménez Díaz, Universidad Autónoma de Madrid, 28040 Madrid, Spain
- CIBERINFEC-Consorcio Centro de Investigación Biomédica en Red (CIBER) de Enfermedades Infecciosas, 28029 Madrid, Spain
| | - Meritxell García-Quintanilla
- Clinical Microbiology Department, IIS-Fundación Jiménez Díaz, Universidad Autónoma de Madrid, 28040 Madrid, Spain
- CIBERINFEC-Consorcio Centro de Investigación Biomédica en Red (CIBER) de Enfermedades Infecciosas, 28029 Madrid, Spain
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9
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Alipour-Khezri E, Moqadami A, Barzegar A, Mahdavi M, Skurnik M, Zarrini G. Bacteriophages and Green Synthesized Zinc Oxide Nanoparticles in Combination Are Efficient against Biofilm Formation of Pseudomonas aeruginosa. Viruses 2024; 16:897. [PMID: 38932188 PMCID: PMC11209622 DOI: 10.3390/v16060897] [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: 04/22/2024] [Revised: 05/29/2024] [Accepted: 05/29/2024] [Indexed: 06/28/2024] Open
Abstract
Bacteriophages (phages) are viruses that infect the bacteria within which their reproduction cycle takes place, a process that ends in the lysis and death of the bacterial cell. Some phages are also able to destroy bacterial biofilms. Due to increased antibiotics resistance, Pseudomonas aeruginosa, another biofilm-forming pathogen, is a problem in many parts of the world. Zinc oxide (ZnO) and other metal nanoparticles (NPs) are biologically active and also possess anti-biofilm properties. ZnO-NPs were prepared by the green synthesis method using orange peels. The vibrational peaks of the ZnO-NPs were analyzed using FTIR analysis, and their size and morphological properties were determined using scanning electron microscopy (SEM). The ability of the ZnO-NPs to reduce or eliminate P. aeruginosa biofilm alone or in combination with phages PB10 and PA19 was investigated. The P. aeruginosa cells were effectively killed in the preformed 48 h biofilms during a 24 h incubation with the ZnO-NP-phage combination, in comparison with the control or ZnO-NPs alone. The treatments on growing biofilms were most efficient in the final stages of biofilm development. All five treatment groups showed a significant biofilm reduction compared to the control group (p < 0.0001) at 48 h of incubation. The influence of the ZnO-NPs and phages on the quorum sensing system of P. aeruginosa was monitored by quantitative real-time PCR (qRT-PCR) of the autoinducer biosynthesis gene lasI. While the ZnO-NPs repressed the lasI gene transcription, the phages slightly activated it at 24 and 48 h of incubation. Also, the effect of the ZnO-NPs and phage PA19 on the viability of HFF2 cells was investigated and the results showed that the combination of NPs with PA19 reduced the toxic effect of ZnO-NPs and also stimulated the growth in normal cells.
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Affiliation(s)
- Elaheh Alipour-Khezri
- Department of Animal Biology, Faculty of Natural Sciences, University of Tabriz, Tabriz 5166616471, Iran; (E.A.-K.); (A.M.); (A.B.)
| | - Amin Moqadami
- Department of Animal Biology, Faculty of Natural Sciences, University of Tabriz, Tabriz 5166616471, Iran; (E.A.-K.); (A.M.); (A.B.)
| | - Abolfazl Barzegar
- Department of Animal Biology, Faculty of Natural Sciences, University of Tabriz, Tabriz 5166616471, Iran; (E.A.-K.); (A.M.); (A.B.)
| | - Majid Mahdavi
- Institute of Biochemistry and Biophysics, University of Tehran, Tehran 1417614335, Iran;
| | - Mikael Skurnik
- Human Microbiome Research Program, and Department of Bacteriology and Immunology, Faculty of Medicine, University of Helsinki, 00290 Helsinki, Finland
| | - Gholamreza Zarrini
- Department of Animal Biology, Faculty of Natural Sciences, University of Tabriz, Tabriz 5166616471, Iran; (E.A.-K.); (A.M.); (A.B.)
- Microbial Biotechnology Research Group, University of Tabriz, Tabriz 5166616471, Iran
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10
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Lu H, Ni SQ. Review on sterilization techniques, and the application potential of phage lyase and lyase immobilization in fighting drug-resistant bacteria. J Mater Chem B 2024; 12:3317-3335. [PMID: 38380677 DOI: 10.1039/d3tb02366d] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/22/2024]
Abstract
Many human health problems and property losses caused by pathogenic contamination cannot be underestimated. Bactericidal techniques have been extensively studied to address this issue of public health and economy. Bacterial resistance develops as a result of the extensive use of single or multiple but persistent usage of sterilizing drugs, and the emergence of super-resistant bacteria brings new challenges. Therefore, it is crucial to control pathogen contamination by applying innovative and effective sterilization techniques. As organisms that exist in nature and can specifically kill bacteria, phages have become the focus as an alternative to antibacterial agents. Furthermore, phage-encoded lyases are proteins that play important roles in phage sterilization. The in vitro sterilization of phage lyase has been developed as a novel biosterilization technique to reduce bacterial resistance and is more environmentally friendly than conventional sterilization treatments. For the shortcomings of enzyme applications, this review discusses the enzyme immobilization methods and the application potential of immobilized lyases for sterilization. Although some techniques provide effective solutions, immobilized lyase sterilization technology has been proven to be a more effective innovation for efficient pathogen killing and reducing bacterial resistance. We hope that this review can provide new insights for the development of sterilization techniques.
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Affiliation(s)
- Han Lu
- School of Environmental Science and Engineering, Shandong University, Qingdao, Shandong 266237, China.
| | - Shou-Qing Ni
- School of Environmental Science and Engineering, Shandong University, Qingdao, Shandong 266237, China.
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Shanmugasundaram S, Nayak N, Puzhankara L, Kedlaya MN, Rajagopal A, Karmakar S. Bacteriophages: the dawn of a new era in periodontal microbiology? Crit Rev Microbiol 2024; 50:212-223. [PMID: 36883683 DOI: 10.1080/1040841x.2023.2182667] [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: 10/31/2022] [Revised: 01/02/2023] [Accepted: 02/15/2023] [Indexed: 03/09/2023]
Abstract
The oral microbiome, populated by a diverse range of species, plays a critical role in the initiation and progression of periodontal disease. The most dominant yet little-discussed players in the microbiome, the bacteriophages, influence the health and disease of the host in various ways. They, not only contribute to periodontal health by preventing the colonization of pathogens and disrupting biofilms but also play a role in periodontal disease by upregulating the virulence of periodontal pathogens through the transfer of antibiotic resistance and virulence factors. Since bacteriophages selectively infect only bacterial cells, they have an enormous scope to be used as a therapeutic strategy; recently, phage therapy has been successfully used to treat antibiotic-resistant systemic infections. Their ability to disrupt biofilms widens the scope against periodontal pathogens and dental plaque biofilms in periodontitis. Future research focussing on the oral phageome and phage therapy's effectiveness and safety could pave way for new avenues in periodontal therapy. This review explores our current understanding of bacteriophages, their interactions in the oral microbiome, and their therapeutic potential in periodontal disease.
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Affiliation(s)
- Shashikiran Shanmugasundaram
- Department of Periodontology, Manipal College of Dental Sciences, Manipal Academy of Higher Education, Manipal, Karnataka, India
| | - Namratha Nayak
- Department of Periodontology, Manipal College of Dental Sciences, Manipal Academy of Higher Education, Manipal, Karnataka, India
| | - Lakshmi Puzhankara
- Department of Periodontology, Manipal College of Dental Sciences, Manipal Academy of Higher Education, Manipal, Karnataka, India
| | - Madhurya N Kedlaya
- Department of Periodontology, Manipal College of Dental Sciences, Manipal Academy of Higher Education, Manipal, Karnataka, India
| | - Anjale Rajagopal
- Department of Periodontology, Manipal College of Dental Sciences, Manipal Academy of Higher Education, Manipal, Karnataka, India
| | - Shaswata Karmakar
- Department of Periodontology, Manipal College of Dental Sciences, Manipal Academy of Higher Education, Manipal, Karnataka, India
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12
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Apostolaki K, Gagaletsios LA, Papagiannitsis CC, Petinaki E. Macrolides impact the growth ability of clinical Pseudomonas aeruginosa through quorum-sensing systems. J Chemother 2024; 36:24-30. [PMID: 38156440 DOI: 10.1080/1120009x.2023.2296150] [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: 09/14/2023] [Accepted: 12/12/2023] [Indexed: 12/30/2023]
Abstract
The aim of the present study was to examine the impact of macrolides on the expression of virulence factors and QS-associated genes in clinical P. aeruginosa isolates. Among 60 clinical P. aeruginosa, pyocyanin production was detected in 27 (45%) isolates, which belonged to various STs. Erythromycin inhibited the production of pigments in 12 out of 27 isolates. Other antibiotic categories didn't have an impact on production of pigments. Additionally, results showed that erythromycin sub-MIC inhibited the growth-rate in 17 isolates. Of note, in six isolates, the inhibition of growth-rate was greater when using both erythromycin and meropenem than using each antibiotic individually. Finally, addition of erythromycin down-regulated the expression of QS-associated genes (65.5%-81.3%) and almost all virulence-associated genes. In conclusion, our results confirmed that macrolides could be used in combination with last-line antibiotics, such as carbapenems, to treat infections caused by multidrug-resistant Gram-negative bacteria.
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Affiliation(s)
| | | | | | - Efthimia Petinaki
- Department of Microbiology, University Hospital of Larissa, Larissa, Greece
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13
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Kulshrestha M, Tiwari M, Tiwari V. Bacteriophage therapy against ESKAPE bacterial pathogens: Current status, strategies, challenges, and future scope. Microb Pathog 2024; 186:106467. [PMID: 38036110 DOI: 10.1016/j.micpath.2023.106467] [Citation(s) in RCA: 3] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/16/2023] [Revised: 10/19/2023] [Accepted: 11/24/2023] [Indexed: 12/02/2023]
Abstract
The ESKAPE pathogens are the primary threat due to their constant spread of drug resistance worldwide. These pathogens are also regarded as opportunistic pathogens and could potentially cause nosocomial infections. Most of the ESKAPE pathogens have developed resistance to almost all the antibiotics that are used against them. Therefore, to deal with antimicrobial resistance, there is an urgent requirement for alternative non-antibiotic strategies to combat this rising issue of drug-resistant organisms. One of the promising alternatives to this scenario is implementing bacteriophage therapy. This under-explored mode of treatment in modern medicine has posed several concerns, such as preferable phages for the treatment, impact on the microbiome (or gut microflora), dose optimisation, safety, etc. The review will cover a rationale for phage therapy, clinical challenges, and propose phage therapy as an effective therapeutic against bacterial coinfections during pandemics. This review also addresses the expected uncertainties for administering the phage as a treatment against the ESKAPE pathogens and the advantages of using lytic phage over temperate, the immune response to phages, and phages in combinational therapies. The interaction between bacteria and bacteriophages in humans and countless animal models can also be used to design novel and futuristic therapeutics like personalised medicine or bacteriophages as anti-biofilm agents. Hence, this review explores different aspects of phage therapy and its potential to emerge as a frontline therapy against the ESKAPE bacterial pathogen.
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Affiliation(s)
- Mukta Kulshrestha
- Department of Biochemistry, Central University of Rajasthan, Ajmer, 305817, India
| | - Monalisa Tiwari
- Department of Biochemistry, Central University of Rajasthan, Ajmer, 305817, India
| | - Vishvanath Tiwari
- Department of Biochemistry, Central University of Rajasthan, Ajmer, 305817, India.
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14
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Olsen NS, Nielsen TK, Cui L, Dedon P, Neve H, Hansen L, Kot W. A novel Queuovirinae lineage of Pseudomonas aeruginosa phages encode dPreQ0 DNA modifications with a single GA motif that provide restriction and CRISPR Cas9 protection in vitro. Nucleic Acids Res 2023; 51:8663-8676. [PMID: 37503841 PMCID: PMC10484667 DOI: 10.1093/nar/gkad622] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/12/2022] [Revised: 06/02/2023] [Accepted: 07/14/2023] [Indexed: 07/29/2023] Open
Abstract
Deazaguanine DNA modifications are widespread in phages, particularly in those with pathogenic hosts. Pseudomonas phage iggy substitutes ∼16.5% of its genomic 2'-deoxyguanosine (G) with dPreQ0, and the iggy deazaguanine transglycosylase (DpdA) is unique in having a strict GA target motif, not observed previously. The iggy PreQ0 modification is shown to provide protection against both restriction endonucleases and Cas9 (when present in PAM), thus expanding our understanding of the deazaguanine modification system, its potential, and diversity. Phage iggy represents a new genus of Pseudomonas phages within the Queuovirinae subfamily; which have very little in common with other published phage genomes in terms of nucleotide similarity (<10%) and common proteins (<2%). Interestingly, shared similarity is concentrated in dpdA and preQ0 biosynthesis genes. TEM imaging confirmed a siphovirus morphology with a prolate icosahedral head and a non-contractile flexible tail with one long central tail spike. The observed protective effect of the deazaguanine modification on the iggy DNA may contribute to its broad within-species host range. Phage iggy was isolated on Pseudomonas aeruginosa PAO1, but also infects PDO300, PAK, PA14, as well as 10 of 27 tested environmental isolates and 13 of 20 tested clinical isolates of P. aeruginosa from patients with cystic fibrosis.
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Affiliation(s)
- Nikoline S Olsen
- Department of Plant and Environmental Sciences, University of Copenhagen, Frederiksberg C, Denmark
| | - Tue K Nielsen
- Department of Plant and Environmental Sciences, University of Copenhagen, Frederiksberg C, Denmark
| | - Liang Cui
- Antimicrobial Resistance Interdisciplinary Research Group, Singapore-MIT Alliance for Research and Technology, Singapore
| | - Peter Dedon
- Antimicrobial Resistance Interdisciplinary Research Group, Singapore-MIT Alliance for Research and Technology, Singapore
- Department of Biological Engineering, Massachusetts Institute of Technology, Cambridge, MA, US
| | - Horst Neve
- Department of Microbiology and Biotechnology, Max Rubner-Institut, Kiel, Germany
| | - Lars H Hansen
- Department of Plant and Environmental Sciences, University of Copenhagen, Frederiksberg C, Denmark
| | - Witold Kot
- Department of Plant and Environmental Sciences, University of Copenhagen, Frederiksberg C, Denmark
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15
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Osman AH, Kotey FCN, Odoom A, Darkwah S, Yeboah RK, Dayie NTKD, Donkor ES. The Potential of Bacteriophage-Antibiotic Combination Therapy in Treating Infections with Multidrug-Resistant Bacteria. Antibiotics (Basel) 2023; 12:1329. [PMID: 37627749 PMCID: PMC10451467 DOI: 10.3390/antibiotics12081329] [Citation(s) in RCA: 18] [Impact Index Per Article: 9.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/20/2023] [Revised: 08/04/2023] [Accepted: 08/05/2023] [Indexed: 08/27/2023] Open
Abstract
The growing threat of antibiotic resistance is a significant global health challenge that has intensified in recent years. The burden of antibiotic resistance on public health is augmented due to its multifaceted nature, as well as the slow-paced and limited development of new antibiotics. The threat posed by resistance is now existential in phage therapy, which had long been touted as a promising replacement for antibiotics. Consequently, it is imperative to explore the potential of combination therapies involving antibiotics and phages as a feasible alternative for treating infections with multidrug-resistant bacteria. Although either bacteriophage or antibiotics can potentially treat bacterial infections, they are each fraught with resistance. Combination therapies, however, yielded positive outcomes in most cases; nonetheless, a few combinations did not show any benefit. Combination therapies comprising the synergistic activity of phages and antibiotics and combinations of phages with other treatments such as probiotics hold promise in the treatment of drug-resistant bacterial infections.
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Affiliation(s)
| | | | | | | | | | | | - Eric S. Donkor
- Department of Medical Microbiology, University of Ghana Medical School, Korle Bu, Accra P.O. Box KB 4236, Ghana; (A.-H.O.); (F.C.N.K.); (A.O.); (S.D.); (R.K.Y.); (N.T.K.D.D.)
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16
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Shariati A, Noei M, Chegini Z. Bacteriophages: The promising therapeutic approach for enhancing ciprofloxacin efficacy against bacterial infection. J Clin Lab Anal 2023:e24932. [PMID: 37377167 PMCID: PMC10388223 DOI: 10.1002/jcla.24932] [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: 02/08/2023] [Revised: 04/14/2023] [Accepted: 06/11/2023] [Indexed: 06/29/2023] Open
Abstract
BACKGROUND The emergence of ciprofloxacin-resistant bacteria is a serious challenge worldwide, bringing the need to find new approaches to manage this bacterium. Bacteriophages (phages) have been shown inhibitory effects against ciprofloxacin-resistance bacteria; thus, ciprofloxacin resistance or tolerance may not affect the phage's infection ability. Additionally, researchers used phage-ciprofloxacin combination therapy for the inhibition of multidrug-resistant bacteria. RESULTS The sublethal concentrations of ciprofloxacin could lead to an increase in progeny production. Antibiotic treatments could enhance the release of progeny phages by shortening the lytic cycle and latent period. Thus, sublethal concentrations of antibiotics combined with phages can be used for the management of bacterial infections with high antibiotic resistance. In addition, combination therapy exerts various selection pressures that can mutually decrease phage and antibiotic resistance. Moreover, phage ciprofloxacin could significantly reduce bacterial counts in the biofilm community. Immediate usage of phages after the attachment of bacteria to the surface of the flow cells, before the development of micro-colonies, could lead to the best effect of phage therapy against bacterial biofilm. Noteworthy, phage should be used before antibiotics usage because this condition may have allowed phage replication to occur first before ciprofloxacin interrupted the bacterial DNA replication process, thereby interfering with the activity of the phages. Furthermore, the phage-ciprofloxacin combination showed a promising result for the management of Pseudomonas aeruginosa infections in mouse models. Nevertheless, low data are existing about the interaction between phages and ciprofloxacin in combination therapies, especially regarding the emergence of phage-resistant mutants. Additionally, there is a challenging and important question of how the combined ciprofloxacin with phages can increase antibacterial functions. Therefore, more examinations are required to support the clinical usage of phage-ciprofloxacin combination therapy.
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Affiliation(s)
- Aref Shariati
- Molecular and Medicine Research Centre, Khomein University of Medical Sciences, Khomein, Iran
| | - Milad Noei
- Department of Genetics, Faculty of Advanced Science and Technology, Tehran Medical Sciences, Islamic Azad University, Tehran, Iran
| | - Zahra Chegini
- Department of Microbiology, School of Medicine, Hamadan University of Medical Sciences, Hamadan, Iran
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Santamaría-Corral G, Senhaji-Kacha A, Broncano-Lavado A, Esteban J, García-Quintanilla M. Bacteriophage-Antibiotic Combination Therapy against Pseudomonas aeruginosa. Antibiotics (Basel) 2023; 12:1089. [PMID: 37508185 PMCID: PMC10376841 DOI: 10.3390/antibiotics12071089] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/04/2023] [Revised: 06/19/2023] [Accepted: 06/20/2023] [Indexed: 07/30/2023] Open
Abstract
Phage therapy is an alternative therapy that is being used as the last resource against infections caused by multidrug-resistant bacteria after the failure of standard treatments. Pseudomonas aeruginosa can cause pneumonia, septicemia, urinary tract, and surgery site infections mainly in immunocompromised people, although it can cause infections in many different patient profiles. Cystic fibrosis patients are particularly vulnerable. In vitro and in vivo studies of phage therapy against P. aeruginosa include both bacteriophages alone and combined with antibiotics. However, the former is the most promising strategy utilized in clinical infections. This review summarizes the recent studies of phage-antibiotic combinations, highlighting the synergistic effects of in vitro and in vivo experiments and successful treatments in patients.
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Affiliation(s)
| | - Abrar Senhaji-Kacha
- Department of Clinical Microbiology, IIS-Fundación Jiménez Díaz, Av. Reyes Católicos 2, 28040 Madrid, Spain
- CIBERINFEC-Infectious Diseases CIBER, 28029 Madrid, Spain
| | - Antonio Broncano-Lavado
- Department of Clinical Microbiology, IIS-Fundación Jiménez Díaz, Av. Reyes Católicos 2, 28040 Madrid, Spain
| | - Jaime Esteban
- Department of Clinical Microbiology, IIS-Fundación Jiménez Díaz, Av. Reyes Católicos 2, 28040 Madrid, Spain
- CIBERINFEC-Infectious Diseases CIBER, 28029 Madrid, Spain
| | - Meritxell García-Quintanilla
- Department of Clinical Microbiology, IIS-Fundación Jiménez Díaz, Av. Reyes Católicos 2, 28040 Madrid, Spain
- CIBERINFEC-Infectious Diseases CIBER, 28029 Madrid, Spain
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18
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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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19
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Sodhi KK, Singh CK, Kumar M, Singh DK. Whole-genome sequencing of Alcaligenes sp. strain MMA: insight into the antibiotic and heavy metal resistant genes. Front Pharmacol 2023; 14:1144561. [PMID: 37251338 PMCID: PMC10213877 DOI: 10.3389/fphar.2023.1144561] [Citation(s) in RCA: 20] [Impact Index Per Article: 10.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/14/2023] [Accepted: 05/02/2023] [Indexed: 05/31/2023] Open
Abstract
Introduction: A wide range of pollutants, including the likes of xenobiotics, heavy metals, and antibiotics, are characteristic of marine ecosystems. The ability of the bacteria to flourish under high metal stress favors the selection of antibiotic resistance in aquatic environments. Increased use and misuse of antibiotics in medicine, agriculture, and veterinary have posed a grave concern over antimicrobial resistance. The exposure to these heavy metals and antibiotics in the bacteria drives the evolution of antibiotic and heavy metal resistance genes. In the earlier study by the author Alcaligenes sp. MMA was involved in the removal of heavy metals and antibiotics. Alcaligenes display diverse bioremediation capabilities but remain unexplored at the level of the genome. Methods: To shed light on its genome, the Alcaligenes sp. strain MMA, was sequenced using Illumina Nova Seq sequencer, which resulted in a draft genome of 3.9 Mb. The genome annotation was done using Rapid annotation using subsystem technology (RAST). Given the spread of antimicrobial resistance and the generation of multi-drug resistant pathogens (MDR), the strain MMA was checked for potential antibiotic and heavy metal resistance genes Further, we checked for the presence of biosynthetic gene clusters in the draft genome. Results: Alcaligenes sp. strain MMA, was sequenced using Illumina Nova Seq sequencer, which resulted in a draft genome of 3.9 Mb. The RAST analysis revealed the presence of 3685 protein-coding genes, involved in the removal of antibiotics and heavy metals. Multiple metal-resistant genes and genes conferring resistance to tetracycline, beta-lactams, and fluoroquinolones were present in the draft genome. Many types of BGCs were predicted, such as siderophore. The secondary metabolites of fungi and bacteria are a rich source of novel bioactive compounds which have the potential to in new drug candidates. Discussion: The results of this study provide information on the strain MMA genome and are valuable for the researcher in further exploitation of the strain MMA for bioremediation. Moreover, whole-genome sequencing has become a useful tool to monitor the spread of antibiotic resistance, a global threat to healthcare.
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Affiliation(s)
| | | | - Mohit Kumar
- Hindu College, University of Delhi, Delhi, India
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20
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Martínez-Gallardo MJ, Villicaña C, Yocupicio-Monroy M, Alcaraz-Estrada SL, León-Félix J. Current knowledge in the use of bacteriophages to combat infections caused by Pseudomonas aeruginosa in cystic fibrosis. Folia Microbiol (Praha) 2023; 68:1-16. [PMID: 35931928 DOI: 10.1007/s12223-022-00990-5] [Citation(s) in RCA: 5] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/28/2022] [Accepted: 07/02/2022] [Indexed: 11/04/2022]
Abstract
Pseudomonas aeruginosa (PA) is considered the first causal agent of morbidity and mortality in people with cystic fibrosis (CF) disease. Multi-resistant strains have emerged due to prolonged treatment with specific antibiotics, so new alternatives have been sought for their control. In this context, there is a renewed interest in therapies based on bacteriophages (phages) supported by several studies suggesting that therapy based on lytic phages and biofilm degraders may be promising for the treatment of lung infections in CF patients. However, there is little clinical data about phage studies in CF and the effectiveness and safety in patients with this disease has not been clear. Therefore, studies regarding on phage characterization, selection, and evaluation in vitro and in vivo models will provide reliable information for designing effective cocktails, either using mixed phages or in combination with antibiotics, making a great progress in clinical research. Hence, this review focuses on the most relevant and recent findings on the activity of lytic phages against PA strains isolated from CF patients and hospital environments, and discusses perspectives on the use of phage therapy on the treatment of PA in CF patients.
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Affiliation(s)
- María José Martínez-Gallardo
- Laboratory of Molecular Biology and Functional Genomics, Centro de Investigación en Alimentación y Desarrollo, Culiacán, Sinaloa, A.C. (CIAD), Mexico
| | - Claudia Villicaña
- CONACYT-Centro de Investigación en Alimentación y Desarrollo A.C. (CIAD), Culiacán, Sinaloa, Mexico
| | - Martha Yocupicio-Monroy
- Postgraduate in Genomic Sciences, Universidad Autónoma de la Ciudad de México (UACM), Mexico City, Mexico
| | | | - Josefina León-Félix
- Laboratory of Molecular Biology and Functional Genomics, Centro de Investigación en Alimentación y Desarrollo, Culiacán, Sinaloa, A.C. (CIAD), Mexico.
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21
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Elois MA, da Silva R, Pilati GVT, Rodríguez-Lázaro D, Fongaro G. Bacteriophages as Biotechnological Tools. Viruses 2023; 15:349. [PMID: 36851563 PMCID: PMC9963553 DOI: 10.3390/v15020349] [Citation(s) in RCA: 15] [Impact Index Per Article: 7.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/22/2022] [Revised: 01/14/2023] [Accepted: 01/18/2023] [Indexed: 01/28/2023] Open
Abstract
Bacteriophages are ubiquitous organisms that can be specific to one or multiple strains of hosts, in addition to being the most abundant entities on the planet. It is estimated that they exceed ten times the total number of bacteria. They are classified as temperate, which means that phages can integrate their genome into the host genome, originating a prophage that replicates with the host cell and may confer immunity against infection by the same type of phage; and lytics, those with greater biotechnological interest and are viruses that lyse the host cell at the end of its reproductive cycle. When lysogenic, they are capable of disseminating bacterial antibiotic resistance genes through horizontal gene transfer. When professionally lytic-that is, obligately lytic and not recently descended from a temperate ancestor-they become allies in bacterial control in ecological imbalance scenarios; these viruses have a biofilm-reducing capacity. Phage therapy has also been advocated by the scientific community, given the uniqueness of issues related to the control of microorganisms and biofilm production when compared to other commonly used techniques. The advantages of using bacteriophages appear as a viable and promising alternative. This review will provide updates on the landscape of phage applications for the biocontrol of pathogens in industrial settings and healthcare.
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Affiliation(s)
- Mariana Alves Elois
- Laboratory of Applied Virology, Department of Microbiology, Immunology and Parasitology, Federal University of Santa Catarina, Florianópolis 88040-900, Brazil
| | - Raphael da Silva
- Laboratory of Applied Virology, Department of Microbiology, Immunology and Parasitology, Federal University of Santa Catarina, Florianópolis 88040-900, Brazil
| | - Giulia Von Tönnemann Pilati
- Laboratory of Applied Virology, Department of Microbiology, Immunology and Parasitology, Federal University of Santa Catarina, Florianópolis 88040-900, Brazil
| | - David Rodríguez-Lázaro
- Microbiology Division, Faculty of Sciences, University of Burgos, 09001 Burgos, Spain
- Research Centre for Emerging Pathogens and Global Health, University of Burgos, 09001 Burgos, Spain
| | - Gislaine Fongaro
- Laboratory of Applied Virology, Department of Microbiology, Immunology and Parasitology, Federal University of Santa Catarina, Florianópolis 88040-900, Brazil
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22
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Abedon ST. Ecology and Evolutionary Biology of Hindering Phage Therapy: The Phage Tolerance vs. Phage Resistance of Bacterial Biofilms. Antibiotics (Basel) 2023; 12:245. [PMID: 36830158 PMCID: PMC9952518 DOI: 10.3390/antibiotics12020245] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/31/2022] [Revised: 01/17/2023] [Accepted: 01/19/2023] [Indexed: 01/27/2023] Open
Abstract
As with antibiotics, we can differentiate various acquired mechanisms of bacteria-mediated inhibition of the action of bacterial viruses (phages or bacteriophages) into ones of tolerance vs. resistance. These also, respectively, may be distinguished as physiological insensitivities (or protections) vs. resistance mutations, phenotypic resistance vs. genotypic resistance, temporary vs. more permanent mechanisms, and ecologically vs. also near-term evolutionarily motivated functions. These phenomena can result from multiple distinct molecular mechanisms, many of which for bacterial tolerance of phages are associated with bacterial biofilms (as is also the case for the bacterial tolerance of antibiotics). The resulting inhibitions are relevant from an applied perspective because of their potential to thwart phage-based treatments of bacterial infections, i.e., phage therapies, as well as their potential to interfere more generally with approaches to the phage-based biological control of bacterial biofilms. In other words, given the generally low toxicity of properly chosen therapeutic phages, it is a combination of phage tolerance and phage resistance, as displayed by targeted bacteria, that seems to represent the greatest impediments to phage therapy's success. Here I explore general concepts of bacterial tolerance of vs. bacterial resistance to phages, particularly as they may be considered in association with bacterial biofilms.
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Affiliation(s)
- Stephen T Abedon
- Department of Microbiology, The Ohio State University, Mansfield, OH 44906, USA
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23
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Mitropoulou G, Koutsokera A, Csajka C, Blanchon S, Sauty A, Brunet JF, von Garnier C, Resch G, Guery B. Phage therapy for pulmonary infections: lessons from clinical experiences and key considerations. Eur Respir Rev 2022; 31:31/166/220121. [PMID: 36198417 DOI: 10.1183/16000617.0121-2022] [Citation(s) in RCA: 16] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/04/2022] [Accepted: 07/27/2022] [Indexed: 11/05/2022] Open
Abstract
Lower respiratory tract infections lead to significant morbidity and mortality. They are increasingly caused by multidrug-resistant pathogens, notably in individuals with cystic fibrosis, hospital-acquired pneumonia and lung transplantation. The use of bacteriophages (phages) to treat bacterial infections is gaining growing attention, with numerous published cases of compassionate treatment over the last few years. Although the use of phages appears safe, the lack of standardisation, the significant heterogeneity of published studies and the paucity of robust efficacy data, alongside regulatory hurdles arising from the existing pharmaceutical legislation, are just some of the challenges phage therapy has to overcome. In this review, we discuss the lessons learned from recent clinical experiences of phage therapy for the treatment of pulmonary infections. We review the key aspects, opportunities and challenges of phage therapy regarding formulations and administration routes, interactions with antibiotics and the immune system, and phage resistance. Building upon the current knowledge base, future pre-clinical studies using emerging technologies and carefully designed clinical trials are expected to enhance our understanding and explore the therapeutic potential of phage therapy.
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Affiliation(s)
- Georgia Mitropoulou
- Division of Pulmonology, Department of Medicine, Lausanne University Hospital, Lausanne, Switzerland .,University of Lausanne, Lausanne, Switzerland.,Shared first authorship
| | - Angela Koutsokera
- Division of Pulmonology, Department of Medicine, Lausanne University Hospital, Lausanne, Switzerland.,University of Lausanne, Lausanne, Switzerland.,Shared first authorship
| | - Chantal Csajka
- Centre for Research and Innovation in Clinical Pharmaceutical Sciences, Lausanne University Hospital, Lausanne, Switzerland.,Institute of Pharmaceutical Sciences of Western Switzerland, University of Geneva, University of Lausanne, Geneva, Switzerland.,School of Pharmaceutical Sciences, University of Geneva, Geneva, Switzerland
| | - Sylvain Blanchon
- University of Lausanne, Lausanne, Switzerland.,Paediatric Pulmonology and Cystic Fibrosis Unit, Division of Paediatrics, Department of Woman-Mother-Child, Lausanne University Hospital, Lausanne, Switzerland
| | - Alain Sauty
- University of Lausanne, Lausanne, Switzerland.,Division of Pulmonology, Neuchâtel Hospital Network, Neuchâtel, Switzerland
| | - Jean-Francois Brunet
- University of Lausanne, Lausanne, Switzerland.,Cell Production Centre, Dept of Interdisciplinary Centres, Lausanne University Hospital, Lausanne, Switzerland
| | - Christophe von Garnier
- Division of Pulmonology, Department of Medicine, Lausanne University Hospital, Lausanne, Switzerland.,University of Lausanne, Lausanne, Switzerland
| | - Grégory Resch
- University of Lausanne, Lausanne, Switzerland.,Centre for Research and Innovation in Clinical Pharmaceutical Sciences, Lausanne University Hospital, Lausanne, Switzerland.,Institute of Pharmaceutical Sciences of Western Switzerland, University of Geneva, University of Lausanne, Geneva, Switzerland.,Shared last authorship
| | - Benoit Guery
- University of Lausanne, Lausanne, Switzerland.,Service of Infectious Diseases, Department of Medicine, Lausanne University Hospital, Lausanne, Switzerland.,Shared last authorship
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24
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Brigmon MM, Brigmon RL. Infectious Diseases Impact on Biomedical Devices and Materials. BIOMEDICAL MATERIALS & DEVICES (NEW YORK, N.Y.) 2022; 1:1-8. [PMID: 38625309 PMCID: PMC9616421 DOI: 10.1007/s44174-022-00035-y] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Subscribe] [Scholar Register] [Received: 07/14/2022] [Accepted: 09/01/2022] [Indexed: 11/07/2022]
Abstract
Infectious diseases and nosocomial infections may play a significant role in healthcare issues associated with biomedical materials and devices. Many current polymer materials employed are inadequate for resisting microbial growth. The increase in microbial antibiotic resistance is also a factor in problematic biomedical implants. In this work, the difficulty in diagnosing biomedical device-related infections is reviewed and how this leads to an increase in microbial antibiotic resistance. A conceptualization of device-related infection pathogenesis and current and future treatments is made. Within this conceptualization, we focus specifically on biofilm formation and the role of host immune and antimicrobial therapies. Using this framework, we describe how current and developing preventative strategies target infectious disease. In light of the significant increase in antimicrobial resistance, we also emphasize the need for parallel development of improved treatment strategies. We also review potential production methods for manufacturing specific nanostructured materials with antimicrobial functionality for implantable devices. Specific examples of both preventative and novel treatments and how they align with the improved care with biomedical devices are described.
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Affiliation(s)
- Matthew M. Brigmon
- Department of Infectious Diseases and Pulmonary Critical Care, Long School of Medicine, UT Health San Antonio, San Antonio, USA
| | - Robin L. Brigmon
- Savannah River National Laboratory, Bldg 999W, Aiken, SC 29808 USA
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25
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Ciofu O, Moser C, Jensen PØ, Høiby N. Tolerance and resistance of microbial biofilms. Nat Rev Microbiol 2022; 20:621-635. [PMID: 35115704 DOI: 10.1038/s41579-022-00682-4] [Citation(s) in RCA: 462] [Impact Index Per Article: 154.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 01/04/2022] [Indexed: 02/07/2023]
Abstract
Chronic infections caused by microbial biofilms represent an important clinical challenge. The recalcitrance of microbial biofilms to antimicrobials and to the immune system is a major cause of persistence and clinical recurrence of these infections. In this Review, we present the extent of the clinical problem, and the mechanisms underlying the tolerance of biofilms to antibiotics and to host responses. We also explore the role of biofilms in the development of antimicrobial resistance mechanisms.
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Affiliation(s)
- Oana Ciofu
- Department of Immunology and Microbiology, Costerton Biofilm Center, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark.
| | - Claus Moser
- Department of Immunology and Microbiology, Costerton Biofilm Center, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark
- Department of Clinical Microbiology, Rigshospitalet, Copenhagen, Denmark
| | - Peter Østrup Jensen
- Department of Immunology and Microbiology, Costerton Biofilm Center, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark
- Department of Clinical Microbiology, Rigshospitalet, Copenhagen, Denmark
| | - Niels Høiby
- Department of Immunology and Microbiology, Costerton Biofilm Center, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark
- Department of Clinical Microbiology, Rigshospitalet, Copenhagen, Denmark
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26
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Venturini C, Petrovic Fabijan A, Fajardo Lubian A, Barbirz S, Iredell J. Biological foundations of successful bacteriophage therapy. EMBO Mol Med 2022; 14:e12435. [PMID: 35620963 PMCID: PMC9260219 DOI: 10.15252/emmm.202012435] [Citation(s) in RCA: 33] [Impact Index Per Article: 11.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/16/2022] [Revised: 04/13/2022] [Accepted: 04/19/2022] [Indexed: 12/20/2022] Open
Abstract
Bacteriophages (phages) are selective viral predators of bacteria. Abundant and ubiquitous in nature, phages can be used to treat bacterial infections (phage therapy), including refractory infections and those resistant to antibiotics. However, despite an abundance of anecdotal evidence of efficacy, significant hurdles remain before routine implementation of phage therapy into medical practice, including a dearth of robust clinical trial data. Phage-bacterium interactions are complex and diverse, characterized by co-evolution trajectories that are significantly influenced by the environments in which they occur (mammalian body sites, water, soil, etc.). An understanding of the molecular mechanisms underpinning these dynamics is essential for successful clinical translation. This review aims to cover key aspects of bacterium-phage interactions that affect bacterial killing by describing the most relevant published literature and detailing the current knowledge gaps most likely to influence therapeutic success.
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Affiliation(s)
- Carola Venturini
- Centre for Infectious Diseases and MicrobiologyWestmead Institute for Medical ResearchWestmeadNSWAustralia
- Faculty of ScienceSydney School of Veterinary ScienceThe University of SydneySydneyNSWAustralia
| | - Aleksandra Petrovic Fabijan
- Centre for Infectious Diseases and MicrobiologyWestmead Institute for Medical ResearchWestmeadNSWAustralia
- Faculty of Health and MedicineSchool of MedicineSydney Medical SchoolThe University of SydneySydneyNSWAustralia
| | - Alicia Fajardo Lubian
- Centre for Infectious Diseases and MicrobiologyWestmead Institute for Medical ResearchWestmeadNSWAustralia
- Faculty of Health and MedicineSchool of MedicineSydney Medical SchoolThe University of SydneySydneyNSWAustralia
| | - Stefanie Barbirz
- Department of MedicineScience FacultyMSB Medical School BerlinBerlinGermany
| | - Jonathan Iredell
- Centre for Infectious Diseases and MicrobiologyWestmead Institute for Medical ResearchWestmeadNSWAustralia
- Faculty of Health and MedicineSchool of MedicineSydney Medical SchoolThe University of SydneySydneyNSWAustralia
- Westmead HospitalWestern Sydney Local Health DistrictWestmeadNSWAustralia
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27
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Visnapuu A, Van der Gucht M, Wagemans J, Lavigne R. Deconstructing the Phage-Bacterial Biofilm Interaction as a Basis to Establish New Antibiofilm Strategies. Viruses 2022; 14:v14051057. [PMID: 35632801 PMCID: PMC9145820 DOI: 10.3390/v14051057] [Citation(s) in RCA: 13] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/01/2021] [Revised: 05/11/2022] [Accepted: 05/11/2022] [Indexed: 12/19/2022] Open
Abstract
The bacterial biofilm constitutes a complex environment that endows the bacterial community within with an ability to cope with biotic and abiotic stresses. Considering the interaction with bacterial viruses, these biofilms contain intrinsic defense mechanisms that protect against phage predation; these mechanisms are driven by physical, structural, and metabolic properties or governed by environment-induced mutations and bacterial diversity. In this regard, horizontal gene transfer can also be a driver of biofilm diversity and some (pro)phages can function as temporary allies in biofilm development. Conversely, as bacterial predators, phages have developed counter mechanisms to overcome the biofilm barrier. We highlight how these natural systems have previously inspired new antibiofilm design strategies, e.g., by utilizing exopolysaccharide degrading enzymes and peptidoglycan hydrolases. Next, we propose new potential approaches including phage-encoded DNases to target extracellular DNA, as well as phage-mediated inhibitors of cellular communication; these examples illustrate the relevance and importance of research aiming to elucidate novel antibiofilm mechanisms contained within the vast set of unknown ORFs from phages.
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28
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Chang C, Yu X, Guo W, Guo C, Guo X, Li Q, Zhu Y. Bacteriophage-Mediated Control of Biofilm: A Promising New Dawn for the Future. Front Microbiol 2022; 13:825828. [PMID: 35495689 PMCID: PMC9048899 DOI: 10.3389/fmicb.2022.825828] [Citation(s) in RCA: 62] [Impact Index Per Article: 20.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/30/2021] [Accepted: 02/11/2022] [Indexed: 12/21/2022] Open
Abstract
Biofilms are complex microbial microcolonies consisting of planktonic and dormant bacteria bound to a surface. The bacterial cells within the biofilm are embedded within the extracellular polymeric substance (EPS) consisting mainly of exopolysaccharides, secreted proteins, lipids, and extracellular DNA. This structural matrix poses a major challenge against common treatment options due to its extensive antibiotic-resistant properties. Because biofilms are so recalcitrant to antibiotics, they pose a unique challenge to patients in a nosocomial setting, mainly linked to lower respiratory, urinary tract, and surgical wound infections as well as the medical devices used during treatment. Another unique property of biofilm is its ability to adhere to both biological and man-made surfaces, allowing growth on human tissues and organs, hospital tools, and medical devices, etc. Based on prior understanding of bacteriophage structure, mechanisms, and its effects on bacteria eradication, leading research has been conducted on the effects of phages and its individual proteins on biofilm and its role in overall biofilm removal while also revealing the obstacles this form of treatment currently have. The expansion in the phage host-species range is one that urges for improvement and is the focus for future studies. This review aims to demonstrate the advantages and challenges of bacteriophage and its components on biofilm removal, as well as potential usage of phage cocktail, combination therapy, and genetically modified phages in a clinical setting.
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Affiliation(s)
- Cheng Chang
- School of Global Health, Chinese Center for Tropical Diseases Research, Shanghai Jiao Tong University School of Medicine, One Health Center, Shanghai Jiao Tong University-The University of Edinburgh, Shanghai, China
| | - Xinbo Yu
- School of Global Health, Chinese Center for Tropical Diseases Research, Shanghai Jiao Tong University School of Medicine, One Health Center, Shanghai Jiao Tong University-The University of Edinburgh, Shanghai, China.,College of Stomatology, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Wennan Guo
- School of Global Health, Chinese Center for Tropical Diseases Research, Shanghai Jiao Tong University School of Medicine, One Health Center, Shanghai Jiao Tong University-The University of Edinburgh, Shanghai, China
| | - Chaoyi Guo
- School of Global Health, Chinese Center for Tropical Diseases Research, Shanghai Jiao Tong University School of Medicine, One Health Center, Shanghai Jiao Tong University-The University of Edinburgh, Shanghai, China
| | - Xiaokui Guo
- School of Global Health, Chinese Center for Tropical Diseases Research, Shanghai Jiao Tong University School of Medicine, One Health Center, Shanghai Jiao Tong University-The University of Edinburgh, Shanghai, China
| | - Qingtian Li
- Department of Laboratory Medicine, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Yongzhang Zhu
- School of Global Health, Chinese Center for Tropical Diseases Research, Shanghai Jiao Tong University School of Medicine, One Health Center, Shanghai Jiao Tong University-The University of Edinburgh, Shanghai, China
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29
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Combination and nanotechnology based pharmaceutical strategies for combating respiratory bacterial biofilm infections. Int J Pharm 2022; 616:121507. [PMID: 35085729 DOI: 10.1016/j.ijpharm.2022.121507] [Citation(s) in RCA: 13] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/15/2021] [Revised: 12/31/2021] [Accepted: 01/20/2022] [Indexed: 12/14/2022]
Abstract
Respiratory infections are one of the major global health problems. Among them, chronic respiratory infections caused by biofilm formation are difficult to treat because of both drug tolerance and poor drug penetration into the complex biofilm structure. A major part of the current research on combating respiratory biofilm infections have been focused on destroying the matrix of extracellular polymeric substance and eDNA of the biofilm or promoting the penetration of antibiotics through the extracellular polymeric substance via delivery technologies in order to kill the bacteria inside. There are also experimental data showing that certain inhaled antibiotics with simple formulations can effectively penetrate EPS to kill surficially located bacteria and centrally located dormant bacteria or persisters. This article aims to review recent advances in the pharmaceutical strategies for combating respiratory biofilm infections with a focus on nanotechnology-based drug delivery approaches. The formation and characteristics of bacterial biofilm infections in the airway mucus are presented, which is followed by a brief review on the current clinical approaches to treat respiratory biofilm infections by surgical removal and antimicrobial therapy, and also the emerging clinical treatment approaches. The current combination of antibiotics and non-antibiotic adjuvants to combat respiratory biofilm infections are also discussed.
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30
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Pouget C, Dunyach-Remy C, Pantel A, Boutet-Dubois A, Schuldiner S, Sotto A, Lavigne JP, Loubet P. Alternative Approaches for the Management of Diabetic Foot Ulcers. Front Microbiol 2021; 12:747618. [PMID: 34675910 PMCID: PMC8524042 DOI: 10.3389/fmicb.2021.747618] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/26/2021] [Accepted: 09/07/2021] [Indexed: 01/13/2023] Open
Abstract
Diabetic foot ulcers (DFU) represent a growing public health problem. The emergence of multidrug-resistant (MDR) bacteria is a complication due to the difficulties in distinguishing between infection and colonization in DFU. Another problem lies in biofilm formation on the skin surface of DFU. Biofilm is an important pathophysiology step in DFU and may contribute to healing delays. Both MDR bacteria and biofilm producing microorganism create hostile conditions to antibiotic action that lead to chronicity of the wound, followed by infection and, in the worst scenario, lower limb amputation. In this context, alternative approaches to antibiotics for the management of DFU would be very welcome. In this review, we discuss current knowledge on biofilm in DFU and we focus on some new alternative solutions for the management of these wounds, such as antibiofilm approaches that could prevent the establishment of microbial biofilms and wound chronicity. These innovative therapeutic strategies could replace or complement the classical strategy for the management of DFU to improve the healing process.
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Affiliation(s)
- Cassandra Pouget
- Virulence Bactérienne et Infections Chroniques, INSERM U1047, Université de Montpellier, Nîmes, France
| | - Catherine Dunyach-Remy
- Virulence Bactérienne et Infections Chroniques, INSERM U1047, Université de Montpellier, Service de Microbiologie et Hygiène Hospitalière, Clinique du Pied Gard Occitanie, CHU Nîmes, Nîmes, France
| | - Alix Pantel
- Virulence Bactérienne et Infections Chroniques, INSERM U1047, Université de Montpellier, Service de Microbiologie et Hygiène Hospitalière, Clinique du Pied Gard Occitanie, CHU Nîmes, Nîmes, France
| | - Adeline Boutet-Dubois
- Virulence Bactérienne et Infections Chroniques, INSERM U1047, Université de Montpellier, Service de Microbiologie et Hygiène Hospitalière, Clinique du Pied Gard Occitanie, CHU Nîmes, Nîmes, France
| | - Sophie Schuldiner
- Virulence Bactérienne et Infections Chroniques, INSERM U1047, Université de Montpellier, Service des Maladies Métaboliques et Endocriniennes, Clinique du Pied Gard Occitanie, CHU Nîmes, Le Grau-du-Roi, France
| | - Albert Sotto
- Virulence Bactérienne et Infections Chroniques, INSERM U1047, Université de Montpellier, Service des Maladies Infectieuses et Tropicales, Clinique du Pied Gard Occitanie, CHU Nîmes, Nîmes, France
| | - Jean-Philippe Lavigne
- Virulence Bactérienne et Infections Chroniques, INSERM U1047, Université de Montpellier, Service de Microbiologie et Hygiène Hospitalière, Clinique du Pied Gard Occitanie, CHU Nîmes, Nîmes, France
| | - Paul Loubet
- Virulence Bactérienne et Infections Chroniques, INSERM U1047, Université de Montpellier, Service des Maladies Infectieuses et Tropicales, Clinique du Pied Gard Occitanie, CHU Nîmes, Nîmes, France
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31
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Fernández-Grajera M, Pacha-Olivenza MA, Gallardo-Moreno AM, González-Martín ML, Pérez-Giraldo C, Fernández-Calderón MC. Modification of physico-chemical surface properties and growth of Staphylococcus aureus under hyperglycemia and ketoacidosis conditions. Colloids Surf B Biointerfaces 2021; 209:112137. [PMID: 34628126 DOI: 10.1016/j.colsurfb.2021.112137] [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: 05/31/2021] [Revised: 08/24/2021] [Accepted: 09/23/2021] [Indexed: 11/26/2022]
Abstract
Diabetes is a widely spread disease affecting the quality of life of millions of people around the world and is associated to a higher risk of developing infections in different parts of the body. The reasons why diabetes enhances infection episodes are not entirely clear; in this study our aim was to explore the changes that one of the most frequently pathogenic bacteria undergoes when exposed to hyperglycemia and ketoacidosis conditions. Physical surface properties such as hydrophobicity and surface electrical charge are related to bacterial growth behavior and the ability of Staphylococcus aureus to form biofilms. The addition of glucose made bacteria more negatively charged and with moderate-intermediate hydrophobicity. Ketone bodies increased hydrophobicity to approximately 75% and pathological concentrations hindered some of the bacterial surface charge by decreasing the negative zeta potential of cells. When both components were present, the bacterial physical surface changes were more similar to those observed in ketone bodies, suggesting a preferential adsorption of ketone bodies over glucose because of the more favorable solubility of glucose in water. Glucose diabetic concentrations gave the highest number of bacteria in the stationary phase of growth and provoked an increase in the biofilm slime index of around 400% in relation to the control state. Also, this situation is related with an increase of bacterial coverage. The combination of a high concentration of glucose and ketone bodies, which corresponds to a poorly controlled diabetic situation, appears associated with an early infection phase; increased hydrophobic attractive force and reduced electrostatic repulsion between cells results in better packing of cells within the biofilm and more efficient retention to the host surface. Knowledge of bacterial response in high amount of glucose and ketoacidosis environments can serve as a basis for designing strategies to prevent bacterial adhesion, biofilm formation and, consequently, the development of infections.
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Affiliation(s)
- María Fernández-Grajera
- University of Extremadura, Department of Applied Physics, Badajoz, Spain; University Institute of Extremadura Sanity Research (INUBE), Badajoz, Spain
| | - Miguel A Pacha-Olivenza
- University Institute of Extremadura Sanity Research (INUBE), Badajoz, Spain; University of Extremadura, Department of Biomedical Science, Badajoz, Spain; Networking Research Center on Bioengineering, Biomaterials and Nanomedicine (CIBER-BBN), Badajoz, Spain.
| | - Amparo M Gallardo-Moreno
- University of Extremadura, Department of Applied Physics, Badajoz, Spain; University Institute of Extremadura Sanity Research (INUBE), Badajoz, Spain; Networking Research Center on Bioengineering, Biomaterials and Nanomedicine (CIBER-BBN), Badajoz, Spain
| | - M Luisa González-Martín
- University of Extremadura, Department of Applied Physics, Badajoz, Spain; University Institute of Extremadura Sanity Research (INUBE), Badajoz, Spain; Networking Research Center on Bioengineering, Biomaterials and Nanomedicine (CIBER-BBN), Badajoz, Spain
| | - Ciro Pérez-Giraldo
- University Institute of Extremadura Sanity Research (INUBE), Badajoz, Spain; University of Extremadura, Department of Biomedical Science, Badajoz, Spain; Networking Research Center on Bioengineering, Biomaterials and Nanomedicine (CIBER-BBN), Badajoz, Spain
| | - M Coronada Fernández-Calderón
- University Institute of Extremadura Sanity Research (INUBE), Badajoz, Spain; University of Extremadura, Department of Biomedical Science, Badajoz, Spain; Networking Research Center on Bioengineering, Biomaterials and Nanomedicine (CIBER-BBN), Badajoz, Spain
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32
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Amankwah S, Abdella K, Kassa T. Bacterial Biofilm Destruction: A Focused Review On The Recent Use of Phage-Based Strategies With Other Antibiofilm Agents. Nanotechnol Sci Appl 2021; 14:161-177. [PMID: 34548785 PMCID: PMC8449863 DOI: 10.2147/nsa.s325594] [Citation(s) in RCA: 46] [Impact Index Per Article: 11.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/19/2021] [Accepted: 08/20/2021] [Indexed: 12/11/2022] Open
Abstract
Biofilms are bacterial communities that live in association with biotic or abiotic surfaces and enclosed in an extracellular polymeric substance. Their formation on both biotic and abiotic surfaces, including human tissue and medical device surfaces, pose a major threat causing chronic infections. In addition, current antibiotics and antiseptic agents have shown limited ability to completely remove biofilms. In this review, the authors provide an overview on the formation of bacterial biofilms and its characteristics, burden and evolution with phages. Moreover, the most recent possible use of phages and phage-derived enzymes to combat bacteria in biofilm structures is elucidated. From the emerging results, it can be concluded that despite successful use of phages and phage-derived products in destroying biofilms, they are mostly not adequate to eradicate all bacterial cells. Nevertheless, a combined therapy with the use of phages and/or phage-derived products with other antimicrobial agents including antibiotics, nanoparticles, and antimicrobial peptides may be effective approaches to remove biofilms from medical device surfaces and to treat their associated infections in humans.
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Affiliation(s)
- Stephen Amankwah
- School of Medical Laboratory Sciences, Institute of Health, Jimma University, Jimma, Ethiopia
- Accra Medical Centre, Accra, Ghana
| | - Kedir Abdella
- School of Medical Laboratory Sciences, Institute of Health, Jimma University, Jimma, Ethiopia
| | - Tesfaye Kassa
- School of Medical Laboratory Sciences, Institute of Health, Jimma University, Jimma, Ethiopia
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33
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Pirnay JP, Ferry T, Resch G. Recent progress towards the implementation of phage therapy in Western medicine. FEMS Microbiol Rev 2021; 46:6325169. [PMID: 34289033 DOI: 10.1093/femsre/fuab040] [Citation(s) in RCA: 49] [Impact Index Per Article: 12.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/16/2020] [Accepted: 07/12/2021] [Indexed: 12/20/2022] Open
Abstract
Like the sword of Damocles, the threat of a post-antibiotic era is hanging over humanity's head. The scientific and medical community is thus reconsidering bacteriophage therapy (BT) as a partial but realistic solution for treatment of difficult to eradicate bacterial infections. Here, we summarize the latest developments in clinical BT applications, with a focus on developments in the following areas: i) pharmacology of bacteriophages of major clinical importance and their synergy with antibiotics; ii) production of therapeutic phages; and iii) clinical trials, case studies, and case reports in the field. We address regulatory concerns, which are of paramount importance insofar as they dictate the conduct of clinical trials, which are needed for broader BT application. The increasing amount of new available data confirm the particularities of BT as being innovative and highly personalized. The current circumstances suggest that the immediate future of BT may be advanced within the framework of national BT centers in collaboration with competent authorities, which are urged to adopt incisive initiatives originally launched by some national regulatory authorities.
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Affiliation(s)
- Jean-Paul Pirnay
- Laboratory for Molecular and Cellular Technology, Queen Astrid Military Hospital, Brussels, Belgium
| | - Tristan Ferry
- Department of Infectious Diseases, Hospices Civils de Lyon, Lyon, France.,CIRI - Centre International de Recherche en Infectiologie, Inserm, U1111, Université Claude Bernard Lyon 1, CNRS, UMR5308, Ecole Normale Supérieure de Lyon, Université de Lyon, Lyon, France
| | - Grégory Resch
- Centre of Research and Innovation in Clinical Pharmaceutical Sciences, Lausanne University Hospital, Lausanne, Switzerland
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34
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Abstract
Bacteriophages and bacterial biofilms are widely present in natural environments, a fact that has accelerated the evolution of phages and their bacterial hosts in these particular niches. Phage-host interactions in biofilm communities are rather complex, where phages are not always merely predators but also can establish symbiotic relationships that induce and strengthen biofilms. In this review we provide an overview of the main features affecting phage-biofilm interactions as well as the currently available methods of studying these interactions. In addition, we address the applications of phages for biofilm control in different contexts.
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Affiliation(s)
- Diana P Pires
- Centre of Biological Engineering, University of Minho, 4710-057 Braga, Portugal;
| | - Luís D R Melo
- Centre of Biological Engineering, University of Minho, 4710-057 Braga, Portugal;
| | - Joana Azeredo
- Centre of Biological Engineering, University of Minho, 4710-057 Braga, Portugal;
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35
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Holger D, Kebriaei R, Morrisette T, Lev K, Alexander J, Rybak M. Clinical Pharmacology of Bacteriophage Therapy: A Focus on Multidrug-Resistant Pseudomonas aeruginosa Infections. Antibiotics (Basel) 2021; 10:556. [PMID: 34064648 PMCID: PMC8151982 DOI: 10.3390/antibiotics10050556] [Citation(s) in RCA: 9] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/20/2021] [Revised: 05/04/2021] [Accepted: 05/07/2021] [Indexed: 12/20/2022] Open
Abstract
Pseudomonas aeruginosa is one of the most common causes of healthcare-associated diseases and is among the top three priority pathogens listed by the World Health Organization (WHO). This Gram-negative pathogen is especially difficult to eradicate because it displays high intrinsic and acquired resistance to many antibiotics. In addition, growing concerns regarding the scarcity of antibiotics against multidrug-resistant (MDR) and extensively drug-resistant (XDR) P. aeruginosa infections necessitate alternative therapies. Bacteriophages, or phages, are viruses that target and infect bacterial cells, and they represent a promising candidate for combatting MDR infections. The aim of this review was to highlight the clinical pharmacology considerations of phage therapy, such as pharmacokinetics, formulation, and dosing, while addressing several challenges associated with phage therapeutics for MDR P. aeruginosa infections. Further studies assessing phage pharmacokinetics and pharmacodynamics will help to guide interested clinicians and phage researchers towards greater success with phage therapy for MDR P. aeruginosa infections.
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Affiliation(s)
- Dana Holger
- Anti-Infective Research Laboratory, Department of Pharmacy Practice, Eugene Applebaum College of Pharmacy and Health Sciences, Wayne State University, Detroit, MI 48201, USA; (D.H.); (R.K.); (T.M.); (K.L.)
| | - Razieh Kebriaei
- Anti-Infective Research Laboratory, Department of Pharmacy Practice, Eugene Applebaum College of Pharmacy and Health Sciences, Wayne State University, Detroit, MI 48201, USA; (D.H.); (R.K.); (T.M.); (K.L.)
| | - Taylor Morrisette
- Anti-Infective Research Laboratory, Department of Pharmacy Practice, Eugene Applebaum College of Pharmacy and Health Sciences, Wayne State University, Detroit, MI 48201, USA; (D.H.); (R.K.); (T.M.); (K.L.)
| | - Katherine Lev
- Anti-Infective Research Laboratory, Department of Pharmacy Practice, Eugene Applebaum College of Pharmacy and Health Sciences, Wayne State University, Detroit, MI 48201, USA; (D.H.); (R.K.); (T.M.); (K.L.)
| | - Jose Alexander
- Department of Microbiology, Virology and Immunology, AdventHealth Central Florida, Orlando, FL 32803, USA;
| | - Michael Rybak
- Anti-Infective Research Laboratory, Department of Pharmacy Practice, Eugene Applebaum College of Pharmacy and Health Sciences, Wayne State University, Detroit, MI 48201, USA; (D.H.); (R.K.); (T.M.); (K.L.)
- Division of Infectious Diseases, Department of Medicine, School of Medicine, Wayne State University, Detroit, MI 48201, USA
- Detroit Medical Center, Department of Pharmacy, Detroit, MI 48201, USA
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Isaev AB, Musharova OS, Severinov KV. Microbial Arsenal of Antiviral Defenses - Part I. BIOCHEMISTRY (MOSCOW) 2021; 86:319-337. [PMID: 33838632 DOI: 10.1134/s0006297921030081] [Citation(s) in RCA: 17] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/29/2022]
Abstract
Bacteriophages or phages are viruses that infect bacterial cells (for the scope of this review we will also consider viruses that infect Archaea). Constant threat of phage infection is a major force that shapes evolution of the microbial genomes. To withstand infection, bacteria had evolved numerous strategies to avoid recognition by phages or to directly interfere with phage propagation inside the cell. Classical molecular biology and genetic engineering have been deeply intertwined with the study of phages and host defenses. Nowadays, owing to the rise of phage therapy, broad application of CRISPR-Cas technologies, and development of bioinformatics approaches that facilitate discovery of new systems, phage biology experiences a revival. This review describes variety of strategies employed by microbes to counter phage infection, with a focus on novel systems discovered in recent years. First chapter covers defense associated with cell surface, role of small molecules, and innate immunity systems relying on DNA modification.
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Affiliation(s)
- Artem B Isaev
- Skolkovo Institute of Science and Technology, Moscow, 143028, Russia.
| | - Olga S Musharova
- Skolkovo Institute of Science and Technology, Moscow, 143028, Russia. .,Institute of Molecular Genetics, Moscow, 119334, Russia
| | - Konstantin V Severinov
- Skolkovo Institute of Science and Technology, Moscow, 143028, Russia. .,Waksman Institute of Microbiology, Piscataway, NJ 08854, USA
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Zalewska-Piątek B, Piątek R. Bacteriophages as Potential Tools for Use in Antimicrobial Therapy and Vaccine Development. Pharmaceuticals (Basel) 2021; 14:331. [PMID: 33916345 PMCID: PMC8066226 DOI: 10.3390/ph14040331] [Citation(s) in RCA: 20] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/04/2021] [Revised: 03/19/2021] [Accepted: 04/02/2021] [Indexed: 12/16/2022] Open
Abstract
The constantly growing number of people suffering from bacterial, viral, or fungal infections, parasitic diseases, and cancers prompts the search for innovative methods of disease prevention and treatment, especially based on vaccines and targeted therapy. An additional problem is the global threat to humanity resulting from the increasing resistance of bacteria to commonly used antibiotics. Conventional vaccines based on bacteria or viruses are common and are generally effective in preventing and controlling various infectious diseases in humans. However, there are problems with the stability of these vaccines, their transport, targeted delivery, safe use, and side effects. In this context, experimental phage therapy based on viruses replicating in bacterial cells currently offers a chance for a breakthrough in the treatment of bacterial infections. Phages are not infectious and pathogenic to eukaryotic cells and do not cause diseases in human body. Furthermore, bacterial viruses are sufficient immuno-stimulators with potential adjuvant abilities, easy to transport, and store. They can also be produced on a large scale with cost reduction. In recent years, they have also provided an ideal platform for the design and production of phage-based vaccines to induce protective host immune responses. The most promising in this group are phage-displayed vaccines, allowing for the display of immunogenic peptides or proteins on the phage surfaces, or phage DNA vaccines responsible for expression of target genes (encoding protective antigens) incorporated into the phage genome. Phage vaccines inducing the production of specific antibodies may in the future protect us against infectious diseases and constitute an effective immune tool to fight cancer. Moreover, personalized phage therapy can represent the greatest medical achievement that saves lives. This review demonstrates the latest advances and developments in the use of phage vaccines to prevent human infectious diseases; phage-based therapy, including clinical trials; and personalized treatment adapted to the patient's needs and the type of bacterial infection. It highlights the advantages and disadvantages of experimental phage therapy and, at the same time, indicates its great potential in the treatment of various diseases, especially those resistant to commonly used antibiotics. All the analyses performed look at the rich history and development of phage therapy over the past 100 years.
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Affiliation(s)
- Beata Zalewska-Piątek
- Department of Molecular Biotechnology and Microbiology, Chemical Faculty, Gdańsk University of Technology, Narutowicza 11/12, 80-233 Gdańsk, Poland;
| | - Rafał Piątek
- Department of Molecular Biotechnology and Microbiology, Chemical Faculty, Gdańsk University of Technology, Narutowicza 11/12, 80-233 Gdańsk, Poland;
- BioTechMed Center, Gdańsk University of Technology, Narutowicza 11/12, 80-233 Gdańsk, Poland
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Pires DP, Costa AR, Pinto G, Meneses L, Azeredo J. Current challenges and future opportunities of phage therapy. FEMS Microbiol Rev 2021; 44:684-700. [PMID: 32472938 DOI: 10.1093/femsre/fuaa017] [Citation(s) in RCA: 153] [Impact Index Per Article: 38.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/23/2020] [Accepted: 05/29/2020] [Indexed: 12/21/2022] Open
Abstract
Antibiotic resistance is a major public health challenge worldwide, whose implications for global health might be devastating if novel antibacterial strategies are not quickly developed. As natural predators of bacteria, (bacterio)phages may play an essential role in escaping such a dreadful future. The rising problem of antibiotic resistance has revived the interest in phage therapy and important developments have been achieved over the last years. But where do we stand today and what can we expect from phage therapy in the future? This is the question we set to answer in this review. Here, we scour the outcomes of human phage therapy clinical trials and case reports, and address the major barriers that stand in the way of using phages in clinical settings. We particularly address the potential of phage resistance to hinder phage therapy and discuss future avenues to explore the full capacity of phage therapy.
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Affiliation(s)
- Diana P Pires
- CEB - Centre of Biological Engineering, University of Minho, Campus de Gualtar, 4710-057, Braga, Portugal
| | - Ana Rita Costa
- Department of Bionanoscience, Kavli Institute of Nanoscience, Delft University of Technology, Van der Maasweg 9, 2629 HZ, Delft, Netherlands
| | - Graça Pinto
- CEB - Centre of Biological Engineering, University of Minho, Campus de Gualtar, 4710-057, Braga, Portugal
| | - Luciana Meneses
- CEB - Centre of Biological Engineering, University of Minho, Campus de Gualtar, 4710-057, Braga, Portugal
| | - Joana Azeredo
- CEB - Centre of Biological Engineering, University of Minho, Campus de Gualtar, 4710-057, Braga, Portugal
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Oliveira VDC, Steixner S, Nascimento CD, Pagnano VO, Silva-Lovato CH, Paranhos HDFO, Wilflingseder D, Coraça-Huber D, Watanabe E. Expression of virulence factors by Pseudomonas aeruginosa biofilm after bacteriophage infection. Microb Pathog 2021; 154:104834. [PMID: 33691179 DOI: 10.1016/j.micpath.2021.104834] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/24/2020] [Revised: 02/16/2021] [Accepted: 02/17/2021] [Indexed: 12/19/2022]
Abstract
The use of bacteriophages for the treatment of bacterial infections has been extensively studied. Nonetheless, the stress response regarding bacteriophage infection and the expression of virulence factors of Pseudomonas aeruginosa after phage infection is poorly discussed. In this study, we evaluated biofilm formation capacity and expression of virulence factors of P. aeruginosa after bacteriophage infection. Biofilm growth rates, biofilm morphology, pyocyanin production and elastase activity were evaluated after 2, 8, 24 and 48 h of co-cultivation with bacteriophages that was recently characterized and showed to be infective towards clinical isolates. In parallel, quantitative real-time polymerase chain reactions were carried out to verify the expression of virulence-related genes. Bacteriophages promoted substantial changes in P. aeruginosa biofilm growth at early co-culture time. In addition, at 8 h, we observed that some cultures developed filaments. Although bacteriophages did not alter both pyocyanin and protease activity, changes on the expression level of genes related to virulence factors were detected. Usually, lasI, pslA, lasB and phzH genes were upregulated after 2 and 48 h of co-culture. These results highlight the need for extensive investigation of pathways and molecules involved in phage infection, since the transcriptional changes would suggest a response activation by P. aeruginosa.
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Affiliation(s)
- Viviane de Cássia Oliveira
- Human Exposome and Infectious Diseases Network - HEID, School of Nursing of Ribeirão Preto, University of São Paulo, Ribeirão Preto, SP, Brazil; Department of Dental Materials and Prostheses, School of Dentistry of Ribeirão Preto, University of São Paulo, Ribeirão Preto, São Paulo, Brazil
| | - Stephan Steixner
- Research Laboratory for Biofilms and Implant Associated Infections (BIOFILM LAB), Department of Orthopedic Surgery, Experimental Orthopedics, Medical University of Innsbruck, Innsbruck, Austria
| | - Cássio do Nascimento
- Department of Dental Materials and Prostheses, School of Dentistry of Ribeirão Preto, University of São Paulo, Ribeirão Preto, São Paulo, Brazil
| | - Valéria Oliveira Pagnano
- Department of Dental Materials and Prostheses, School of Dentistry of Ribeirão Preto, University of São Paulo, Ribeirão Preto, São Paulo, Brazil
| | - Cláudia Helena Silva-Lovato
- Department of Dental Materials and Prostheses, School of Dentistry of Ribeirão Preto, University of São Paulo, Ribeirão Preto, São Paulo, Brazil
| | - Helena de Freitas Oliveira Paranhos
- Department of Dental Materials and Prostheses, School of Dentistry of Ribeirão Preto, University of São Paulo, Ribeirão Preto, São Paulo, Brazil
| | - Doris Wilflingseder
- Division of Hygiene and Medical Microbiology, Medical University of Innsbruck, Innsbruck, Austria
| | - Débora Coraça-Huber
- Research Laboratory for Biofilms and Implant Associated Infections (BIOFILM LAB), Department of Orthopedic Surgery, Experimental Orthopedics, Medical University of Innsbruck, Innsbruck, Austria
| | - Evandro Watanabe
- Human Exposome and Infectious Diseases Network - HEID, School of Nursing of Ribeirão Preto, University of São Paulo, Ribeirão Preto, SP, Brazil; Department of Restorative Dentistry, School of Dentistry of Ribeirão Preto, University of São Paulo, São Paulo, Brazil.
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Oliveira VC, Macedo AP, Melo LDR, Santos SB, Hermann PRS, Silva-Lovato CH, Paranhos HFO, Andrade D, Watanabe E. Bacteriophage Cocktail-Mediated Inhibition of Pseudomonas aeruginosa Biofilm on Endotracheal Tube Surface. Antibiotics (Basel) 2021; 10:78. [PMID: 33467548 PMCID: PMC7830274 DOI: 10.3390/antibiotics10010078] [Citation(s) in RCA: 12] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/01/2020] [Revised: 01/04/2021] [Accepted: 01/12/2021] [Indexed: 02/06/2023] Open
Abstract
Although different strategies to control biofilm formation on endotracheal tubes have been proposed, there are scarce scientific data on applying phages for both removing and preventing Pseudomonas aeruginosa biofilms on the device surface. Here, the anti-biofilm capacity of five bacteriophages was evaluated by a high content screening assay. We observed that biofilms were significantly reduced after phage treatment, especially in multidrug-resistant strains. Considering the anti-biofilm screens, two phages were selected as cocktail components, and the cocktail's ability to prevent colonization of the endotracheal tube surface was tested in a dynamic biofilm model. Phage-coated tubes were challenged with different P. aeruginosa strains. The biofilm growth was monitored from 24 to 168 h by colony forming unit counting, metabolic activity assessment, and biofilm morphology observation. The phage cocktail promoted differences of bacterial colonization; nonetheless, the action was strain dependent. Phage cocktail coating did not promote substantial changes in metabolic activity. Scanning electron microscopy revealed a higher concentration of biofilm cells in control, while tower-like structures could be observed on phage cocktail-coated tubes. These results demonstrate that with the development of new coating strategies, phage therapy has potential in controlling the endotracheal tube-associated biofilm.
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Affiliation(s)
- Viviane C. Oliveira
- Human Exposome and Infectious Diseases Network—HEID, School of Nursing of Ribeirão Preto, University of São Paulo, Bandeirantes Avenue 3900, Ribeirão Preto, São Paulo 14040-904, Brazil; (V.C.O.); (P.R.S.H.); (D.A.)
- Department of Dental Materials and Prostheses, School of Dentistry of Ribeirão Preto, University of São Paulo, Café Avenue S/N, Ribeirão Preto, São Paulo 14040-904, Brazil; (A.P.M.); (C.H.S.-L.); (H.F.O.P.)
| | - Ana P. Macedo
- Department of Dental Materials and Prostheses, School of Dentistry of Ribeirão Preto, University of São Paulo, Café Avenue S/N, Ribeirão Preto, São Paulo 14040-904, Brazil; (A.P.M.); (C.H.S.-L.); (H.F.O.P.)
| | - Luís D. R. Melo
- Centre of Biological Engineering—CEB, University of Minho, 4710-057 Braga, Portugal; (L.D.R.M.); (S.B.S.)
| | - Sílvio B. Santos
- Centre of Biological Engineering—CEB, University of Minho, 4710-057 Braga, Portugal; (L.D.R.M.); (S.B.S.)
| | - Paula R. S. Hermann
- Human Exposome and Infectious Diseases Network—HEID, School of Nursing of Ribeirão Preto, University of São Paulo, Bandeirantes Avenue 3900, Ribeirão Preto, São Paulo 14040-904, Brazil; (V.C.O.); (P.R.S.H.); (D.A.)
- Department of Nursing, University of Brasília, Distrito Federal, Brasília 72220-275, Brazil
| | - Cláudia H. Silva-Lovato
- Department of Dental Materials and Prostheses, School of Dentistry of Ribeirão Preto, University of São Paulo, Café Avenue S/N, Ribeirão Preto, São Paulo 14040-904, Brazil; (A.P.M.); (C.H.S.-L.); (H.F.O.P.)
| | - Helena F. O. Paranhos
- Department of Dental Materials and Prostheses, School of Dentistry of Ribeirão Preto, University of São Paulo, Café Avenue S/N, Ribeirão Preto, São Paulo 14040-904, Brazil; (A.P.M.); (C.H.S.-L.); (H.F.O.P.)
| | - Denise Andrade
- Human Exposome and Infectious Diseases Network—HEID, School of Nursing of Ribeirão Preto, University of São Paulo, Bandeirantes Avenue 3900, Ribeirão Preto, São Paulo 14040-904, Brazil; (V.C.O.); (P.R.S.H.); (D.A.)
| | - Evandro Watanabe
- Human Exposome and Infectious Diseases Network—HEID, School of Nursing of Ribeirão Preto, University of São Paulo, Bandeirantes Avenue 3900, Ribeirão Preto, São Paulo 14040-904, Brazil; (V.C.O.); (P.R.S.H.); (D.A.)
- Department of Restorative Dentistry, School of Dentistry of Ribeirão Preto, University of São Paulo, Café Avenue S/N, Ribeirão Preto, São Paulo 14040-904, Brazil
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41
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Davis CM, McCutcheon JG, Dennis JJ. Aztreonam Lysine Increases the Activity of Phages E79 and phiKZ against Pseudomonas aeruginosa PA01. Microorganisms 2021; 9:microorganisms9010152. [PMID: 33445453 PMCID: PMC7827458 DOI: 10.3390/microorganisms9010152] [Citation(s) in RCA: 19] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/17/2020] [Revised: 01/05/2021] [Accepted: 01/08/2021] [Indexed: 02/07/2023] Open
Abstract
Pseudomonas aeruginosa is a pernicious bacterial pathogen that is difficult to treat because of high levels of antibiotic resistance. A promising alternative treatment option for such bacteria is the application of bacteriophages; the correct combination of phages plus antibiotics can produce synergistic inhibitory effects. In this study, we describe morphological changes induced by sub-MIC levels of the antibiotic aztreonam lysine (AzLys) on P. aeruginosa PA01, which may in part explain the observed phage–antibiotic synergy (PAS). One-step growth curves for phage E79 showed increased adsorption rates, decreased infection latency, accelerated time to lysis and a minor reduction in burst size. Phage E79 plus AzLys PAS was also able to significantly reduce P. aeruginosa biofilm growth over 3-fold as compared to phage treatment alone. Sub-inhibitory AzLys-induced filamentation of P. aeruginosa cells resulted in loss of twitching motility and a reduction in swimming motility, likely due to a reduction in the number of polar Type IV pili and flagella, respectively, on the filamented cell surfaces. Phage phiKZ, which uses Type IV pili as a receptor, did not exhibit increased activity with AzLys at lower sub-inhibitory levels, but still produced phage–antibiotic synergistic killing with sub-inhibitory AzLys. A one-step growth curve indicates that phiKZ in the presence of AzLys also exhibits a decreased infection latency and moderately undergoes accelerated time to lysis. In contrast to prior PAS studies demonstrating that phages undergo delayed time to lysis with cell filamentation, these PAS results show that phages undergo accelerated time to lysis, which therefore suggests that PAS is dependent upon multiple factors, including the type of phages and antibiotics used, and the bacterial host being tested.
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42
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Lin Y, Quan D, Chang RYK, Chow MYT, Wang Y, Li M, Morales S, Britton WJ, Kutter E, Li J, Chan HK. Synergistic activity of phage PEV20-ciprofloxacin combination powder formulation-A proof-of-principle study in a P. aeruginosa lung infection model. Eur J Pharm Biopharm 2020; 158:166-171. [PMID: 33253892 DOI: 10.1016/j.ejpb.2020.11.019] [Citation(s) in RCA: 31] [Impact Index Per Article: 6.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/16/2020] [Revised: 11/15/2020] [Accepted: 11/24/2020] [Indexed: 12/18/2022]
Abstract
Combination treatment using bacteriophage and antibiotics is potentially an advanced approach to combatting antimicrobial-resistant bacterial infections. We have recently developed an inhalable powder by co-spray drying Pseudomonas phage PEV20 with ciprofloxacin. The purpose of this study was to assess the in vivo effect of the powder using a neutropenic mouse model of acute lung infection. The synergistic activity of PEV20 and ciprofloxacin was investigated by infecting mice with P. aeruginosa, then administering freshly spray-dried single PEV20 (106 PFU/mg), single ciprofloxacin (0.33 mg/mg) or combined PEV20-ciprofloxacin treatment using a dry powder insufflator. Lung tissues were then harvested for colony counting and flow cytometry analysis at 24 h post-treatment. PEV20 and ciprofloxacin combination powder significantly reduced the bacterial load of clinical P. aeruginosa strain in mouse lungs by 5.9 log10 (p < 0.005). No obvious reduction in the bacterial load was observed when the animals were treated only with PEV20 or ciprofloxacin. Assessment of immunological responses in the lungs showed reduced inflammation associating with the bactericidal effect of the PEV20-ciprofloxacin powder. In conclusion, this study has demonstrated the synergistic potential of using the combination PEV20-ciprofloxacin powder for P. aeruginosa respiratory infections.
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Affiliation(s)
- Yu Lin
- Advanced Drug Delivery Group, School of Pharmacy, Faculty of Medicine and Health, University of Sydney, Sydney, NSW, Australia
| | - Diana Quan
- Centenary Institute and Faculty of Medicine and Health, University of Sydney, Sydney, NSW, Australia
| | - Rachel Yoon Kyung Chang
- Advanced Drug Delivery Group, School of Pharmacy, Faculty of Medicine and Health, University of Sydney, Sydney, NSW, Australia
| | - Michael Y T Chow
- Advanced Drug Delivery Group, School of Pharmacy, Faculty of Medicine and Health, University of Sydney, Sydney, NSW, Australia
| | - Yuncheng Wang
- Advanced Drug Delivery Group, School of Pharmacy, Faculty of Medicine and Health, University of Sydney, Sydney, NSW, Australia
| | - Mengyu Li
- Advanced Drug Delivery Group, School of Pharmacy, Faculty of Medicine and Health, University of Sydney, Sydney, NSW, Australia
| | | | - Warwick J Britton
- Centenary Institute and Faculty of Medicine and Health, University of Sydney, Sydney, NSW, Australia
| | | | - Jian Li
- Monash Biomedicine Discovery Institute, Department of Microbiology, Monash University, Clayton, Victoria, Australia
| | - Hak-Kim Chan
- Advanced Drug Delivery Group, School of Pharmacy, Faculty of Medicine and Health, University of Sydney, Sydney, NSW, Australia.
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43
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Chegini Z, Khoshbayan A, Taati Moghadam M, Farahani I, Jazireian P, Shariati A. Bacteriophage therapy against Pseudomonas aeruginosa biofilms: a review. Ann Clin Microbiol Antimicrob 2020; 19:45. [PMID: 32998720 PMCID: PMC7528332 DOI: 10.1186/s12941-020-00389-5] [Citation(s) in RCA: 143] [Impact Index Per Article: 28.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/07/2020] [Accepted: 09/23/2020] [Indexed: 12/14/2022] Open
Abstract
Multi-Drug Resistant (MDR) Pseudomonas aeruginosa is one of the most important bacterial pathogens that causes infection with a high mortality rate due to resistance to different antibiotics. This bacterium prompts extensive tissue damage with varying factors of virulence, and its biofilm production causes chronic and antibiotic-resistant infections. Therefore, due to the non-applicability of antibiotics for the destruction of P. aeruginosa biofilm, alternative approaches have been considered by researchers, and phage therapy is one of these new therapeutic solutions. Bacteriophages can be used to eradicate P. aeruginosa biofilm by destroying the extracellular matrix, increasing the permeability of antibiotics into the inner layer of biofilm, and inhibiting its formation by stopping the quorum-sensing activity. Furthermore, the combined use of bacteriophages and other compounds with anti-biofilm properties such as nanoparticles, enzymes, and natural products can be of more interest because they invade the biofilm by various mechanisms and can be more effective than the one used alone. On the other hand, the use of bacteriophages for biofilm destruction has some limitations such as limited host range, high-density biofilm, sub-populate phage resistance in biofilm, and inhibition of phage infection via quorum sensing in biofilm. Therefore, in this review, we specifically discuss the use of phage therapy for inhibition of P. aeruginosa biofilm in clinical and in vitro studies to identify different aspects of this treatment for broader use.
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Affiliation(s)
- Zahra Chegini
- Department of Microbiology, School of Medicine, Iran University of Medical Sciences, Tehran, Iran
| | - Amin Khoshbayan
- Student Research Committee, Iran University of Medical Sciences, Tehran, Iran
| | - Majid Taati Moghadam
- Department of Microbiology, School of Medicine, Iran University of Medical Sciences, Tehran, Iran
| | - Iman Farahani
- Molecular and Medicine Research Center, Department of Microbiology and Immunology, School of Medicine, Arak University of Medical Sciences, Arak, Iran
| | - Parham Jazireian
- Department of Genetics, Reproductive Biomedicine Research Center, Royan Institute for Reproductive Biomedicine, ACECR, Tehran, Iran
| | - Aref Shariati
- Department of Microbiology, School of Medicine, Shahid Beheshti University of Medical Sciences, Tehran, Iran.
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Abstract
To formulate the optimal strategy of combatting bacterial biofilms, in this review we update current knowledge on the growing problem of biofilm formation and its resistance to antibiotics which has spurred the search for new strategies to deal with this complication. Based on recent findings, the role of bacteriophages in the prevention and elimination of biofilm-related infections has been emphasized. In vitro, ex vivo and in vivo biofilm treatment models with single bacteriophages or phage cocktails have been compared. A combined use of bacteriophages with antibiotics in vitro or in vivo confirms earlier reports of the synergistic effect of these agents in improving biofilm removal. Furthermore, studies on the application of phage-derived lysins in vitro, ex vivo or in vivo against biofilm-related infections are encouraging. The strategy of combined use of phage and antibiotics seems to be different from using lysins and antibiotics. These findings suggest that phages and lysins alone or in combination with antibiotics may be an efficient weapon against biofilm formation in vivo and ex vivo, which could be useful in formulating novel strategies to combat bacterial infections. Those findings proved to be relevant in the prevention and destruction of biofilms occurring during urinary tract infections, orthopedic implant-related infections, periodontal and peri-implant infections. In conclusion, it appears that most efficient strategy of eliminating biofilms involves phages or lysins in combination with antibiotics, but the optimal scheme of their administration requires further studies.
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Abstract
This work develops and analyzes a novel model of phage-antibiotic combination therapy, specifically adapted to an in vivo context. The objective is to explore the underlying basis for clinical application of combination therapy utilizing bacteriophage that target antibiotic efflux pumps in Pseudomonas aeruginosa. In doing so, the paper addresses three key questions. How robust is combination therapy to variation in the resistance profiles of pathogens? What is the role of immune responses in shaping therapeutic outcomes? What levels of phage and antibiotics are necessary for curative success? As we show, combination therapy outperforms either phage or antibiotic alone, and therapeutic effectiveness is enhanced given interaction with innate immune responses. Notably, therapeutic success can be achieved even at subinhibitory concentrations of antibiotic. These in silico findings provide further support to the nascent application of combination therapy to treat MDR bacterial infections, while highlighting the role of system-level feedbacks in shaping therapeutic outcomes. The spread of multidrug-resistant (MDR) bacteria is a global public health crisis. Bacteriophage therapy (or “phage therapy”) constitutes a potential alternative approach to treat MDR infections. However, the effective use of phage therapy may be limited when phage-resistant bacterial mutants evolve and proliferate during treatment. Here, we develop a nonlinear population dynamics model of combination therapy that accounts for the system-level interactions between bacteria, phage, and antibiotics for in vivo application given an immune response against bacteria. We simulate the combination therapy model for two strains of Pseudomonas aeruginosa, one which is phage sensitive (and antibiotic resistant) and one which is antibiotic sensitive (and phage resistant). We find that combination therapy outperforms either phage or antibiotic alone and that therapeutic effectiveness is enhanced given interaction with innate immune responses. Notably, therapeutic success can be achieved even at subinhibitory concentrations of antibiotics, e.g., ciprofloxacin. These in silico findings provide further support to the nascent application of combination therapy to treat MDR bacterial infections, while highlighting the role of innate immunity in shaping therapeutic outcomes. IMPORTANCE This work develops and analyzes a novel model of phage-antibiotic combination therapy, specifically adapted to an in vivo context. The objective is to explore the underlying basis for clinical application of combination therapy utilizing bacteriophage that target antibiotic efflux pumps in Pseudomonas aeruginosa. In doing so, the paper addresses three key questions. How robust is combination therapy to variation in the resistance profiles of pathogens? What is the role of immune responses in shaping therapeutic outcomes? What levels of phage and antibiotics are necessary for curative success? As we show, combination therapy outperforms either phage or antibiotic alone, and therapeutic effectiveness is enhanced given interaction with innate immune responses. Notably, therapeutic success can be achieved even at subinhibitory concentrations of antibiotic. These in silico findings provide further support to the nascent application of combination therapy to treat MDR bacterial infections, while highlighting the role of system-level feedbacks in shaping therapeutic outcomes.
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Gajdács M, Spengler G. The Role of Drug Repurposing in the Development of Novel Antimicrobial Drugs: Non-Antibiotic Pharmacological Agents as Quorum Sensing-Inhibitors. Antibiotics (Basel) 2019; 8:E270. [PMID: 31861228 PMCID: PMC6963710 DOI: 10.3390/antibiotics8040270] [Citation(s) in RCA: 37] [Impact Index Per Article: 6.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/10/2019] [Revised: 12/11/2019] [Accepted: 12/12/2019] [Indexed: 02/06/2023] Open
Abstract
Background: The emergence of multidrug-resistant organisms (MDROs) is a global public health issue, severely hindering clinicians in administering appropriate antimicrobial therapy. Drug repurposing is a drug development strategy, during which new pharmacological applications are identified for already approved drugs. From the viewpoint of the development of virulence inhibitors, inhibition of quorum sensing (QS) is a promising route because various important features in bacterial physiology and virulence are mediated by QS-dependent gene expression. Methods: Forty-five pharmacological agents, encompassing a wide variety of different chemical structures and mechanisms of action, were tested during our experiments. The antibacterial activity of the compounds was tested using the broth microdilution method. Screening and semi-quantitative assessment of QS-inhibition by the compounds was performed using QS-signal molecule-producing and indicator strains. Results: Fourteen pharmaceutical agents showed antibacterial activity in the tested concentration range, while eight drugs (namely 5-fluorouracil, metamizole-sodium, cisplatin, methotrexate, bleomycin, promethazine, chlorpromazine, and thioridazine) showed dose-dependent QS-inhibitory activity in the in vitro model systems applied during the experiments. Conclusions: Virulence inhibitors represent an attractive alternative strategy to combat bacterial pathogens more efficiently. Some of the tested compounds could be considered potential QS-inhibitory agents, warranting further experiments involving additional model systems to establish the extent of their efficacy.
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Affiliation(s)
- Márió Gajdács
- Department of Medical Microbiology and Immunobiology, Faculty of Medicine, University of Szeged, Dóm tér 10, 6720 Szeged, Hungary
- Department of Pharmacodynamics and Biopharmacy, Faculty of Pharmacy, University of Szeged, Eötvös utca 6, 6720 Szeged, Hungary;
| | - Gabriella Spengler
- Department of Pharmacodynamics and Biopharmacy, Faculty of Pharmacy, University of Szeged, Eötvös utca 6, 6720 Szeged, Hungary;
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Affiliation(s)
- Juliet Roshini Mohan Raj
- Nitte University Centre for Science Education and Research, Nitte (Deemed to be University), Mangaluru, India
| | - Indrani Karunasagar
- Nitte University Centre for Science Education and Research, Nitte (Deemed to be University), Mangaluru, India
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Dąbrowska K, Abedon ST. Pharmacologically Aware Phage Therapy: Pharmacodynamic and Pharmacokinetic Obstacles to Phage Antibacterial Action in Animal and Human Bodies. Microbiol Mol Biol Rev 2019; 83:e00012-19. [PMID: 31666296 PMCID: PMC6822990 DOI: 10.1128/mmbr.00012-19] [Citation(s) in RCA: 99] [Impact Index Per Article: 16.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/20/2022] Open
Abstract
The use of viruses infecting bacteria (bacteriophages or phages) to treat bacterial infections has been ongoing clinically for approximately 100 years. Despite that long history, the growing international crisis of resistance to standard antibiotics, abundant anecdotal evidence of efficacy, and one successful modern clinical trial of efficacy, this phage therapy is not yet a mainstream approach in medicine. One explanation for why phage therapy has not been subject to more widespread implementation is that phage therapy research, both preclinical and clinical, can be insufficiently pharmacologically aware. Consequently, here we consider the pharmacological obstacles to phage therapy effectiveness, with phages in phage therapy explicitly being considered to serve as drug equivalents. The study of pharmacology has traditionally been differentiated into pharmacokinetic and pharmacodynamic aspects. We therefore separately consider the difficulties that phages as virions can have in traveling through body compartments toward reaching their target bacteria (pharmacokinetics) and the difficulties that phages can have in exerting antibacterial activity once they have reached those bacteria (pharmacodynamics). The latter difficulties, at least in part, are functions of phage host range and bacterial resistance to phages. Given the apparently low toxicity of phages and the minimal side effects of phage therapy as practiced, phage therapy should be successful so long as phages can reach the targeted bacteria in sufficiently high numbers, adsorb, and then kill those bacteria. Greater awareness of what obstacles to this success generally or specifically can exist, as documented in this review, should aid in the further development of phage therapy toward wider use.
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Affiliation(s)
- Krystyna Dąbrowska
- Bacteriophage Laboratory, Institute of Immunology and Experimental Therapy, Polish Academy of Sciences, Wrocław, Poland
| | - Stephen T Abedon
- Department of Microbiology, The Ohio State University, Mansfield, Ohio, USA
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Abedon ST. Phage-Antibiotic Combination Treatments: Antagonistic Impacts of Antibiotics on the Pharmacodynamics of Phage Therapy? Antibiotics (Basel) 2019; 8:antibiotics8040182. [PMID: 31614449 PMCID: PMC6963693 DOI: 10.3390/antibiotics8040182] [Citation(s) in RCA: 75] [Impact Index Per Article: 12.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/27/2019] [Revised: 10/02/2019] [Accepted: 10/03/2019] [Indexed: 12/12/2022] Open
Abstract
Bacteria can evolve resistance to antibiotics. Even without changing genetically, bacteria also can display tolerance to antibiotic treatments. Many antibiotics are also broadly acting, as can result in excessive modifications of body microbiomes. Particularly for antibiotics of last resort or in treating extremely ill patients, antibiotics furthermore can display excessive toxicities. Antibiotics nevertheless remain the standard of care for bacterial infections, and rightly so given their long track records of both antibacterial efficacy and infrequency of severe side effects. Antibiotics do not successfully cure all treated bacterial infections, however, thereby providing a utility to alternative antibacterial approaches. One such approach is the use of bacteriophages, the viruses of bacteria. This nearly 100-year-old bactericidal, anti-infection technology can be effective against antibiotic-resistant or -tolerant bacteria, including bacterial biofilms and persister cells. Ideally phages could be used in combination with standard antibiotics while retaining their anti-bacterial pharmacodynamic activity, this despite antibiotics interfering with aspects of bacterial metabolism that are also required for full phage infection activity. Here I examine the literature of pre-clinical phage-antibiotic combination treatments, with emphasis on antibiotic-susceptible bacterial targets. I review evidence of antibiotic interference with phage infection activity along with its converse: phage antibacterial functioning despite antibiotic presence.
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Affiliation(s)
- Stephen T Abedon
- Department of Microbiology, The Ohio State University, Mansfield, OH 44906, USA.
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Big Impact of the Tiny: Bacteriophage-Bacteria Interactions in Biofilms. Trends Microbiol 2019; 27:739-752. [PMID: 31128928 DOI: 10.1016/j.tim.2019.04.006] [Citation(s) in RCA: 85] [Impact Index Per Article: 14.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/15/2019] [Revised: 04/10/2019] [Accepted: 04/19/2019] [Indexed: 01/17/2023]
Abstract
Bacteriophages (phages) have been shaping bacterial ecology and evolution for millions of years, for example, by selecting for defence strategies. Evidence supports that bacterial biofilm formation is one such strategy and that biofilm-mediated protection against phage infection depends on maturation and composition of the extracellular matrix. Interestingly, studies have revealed that phages can induce and strengthen biofilms. Here we review interactions between bacteria and phages in biofilms, discuss the underlying mechanisms, the potential of phage therapy for biofilm control, and emphasize the importance of considering biofilms in future phage research. This is especially relevant as biofilms are associated with increased tolerance towards antibiotics and are implicated in the majority of chronic infections.
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