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Zhao Y, He L, Sun L, Liu W, Wang H, Zhang J, Gong Y, Wang X. RdxA-independent mechanism of Helicobacter pylori metronidazole metabolism. Front Microbiol 2025; 16:1553734. [PMID: 40207148 PMCID: PMC11979234 DOI: 10.3389/fmicb.2025.1553734] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/31/2024] [Accepted: 03/13/2025] [Indexed: 04/11/2025] Open
Abstract
Introduction Metronidazole (MNZ) is widely used to treat Helicobacter pylori infection worldwide. However, due to excessive and repeated use, resistance rates have exceeded 90% in some regions. The mechanisms of MNZ resistance have been extensively studied, and RdxA has been identified as the primary enzyme responsible for MNZ activation. Mutations in RdxA, particularly termination mutations, can lead to high-level MNZ resistance. Methods We identified a strain, ICDC15003s, which harbored RdxA termination mutation but remained highly susceptible to MNZ. To explore this phenomenon, we conducted comparative genomic and transcriptomic analyses to define RdxA-independent mechanisms of MNZ metabolism. Results and discussion We found missense mutations in genes such as yfkO, acxB, alr1, glk, and cobB. Additionally, the expression of multiple genes, including TonB-dependent receptor and mod, significantly changed in resistant strains. Notably, the sequences and expression levels of known nitroreductases like FrxA and FdxB remained unchanged after induction of MNZ resistance, suggesting they were not responsible for MNZ sensitivity in ICDC15003s. Instead, transcriptional alterations were observed in genes encoding NADH-quinone oxidoreductase subunit (M, J, H and K), suggesting a potential compensatory mechanism for the loss of RdxA activity. We proposed that NADH-quinone oxidoreductase might serve as an RdxA-independent mechanism for MNZ metabolism and resistance through regulation of its expression levels. This discovery could provide new strategies to address MNZ resistance and aid in developing nitroimidazole antibiotics.
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Affiliation(s)
- Yakun Zhao
- National Key Laboratory of Intelligent Tracking and Forecasting for Infectious Diseases, National Institute for Communicable Disease Control and Prevention, Chinese Center for Disease Control and Prevention, Beijing, China
- Department of Health Statistics, China Medical University, Shenyang, China
| | - Lihua He
- National Key Laboratory of Intelligent Tracking and Forecasting for Infectious Diseases, National Institute for Communicable Disease Control and Prevention, Chinese Center for Disease Control and Prevention, Beijing, China
| | - Lu Sun
- National Key Laboratory of Intelligent Tracking and Forecasting for Infectious Diseases, National Institute for Communicable Disease Control and Prevention, Chinese Center for Disease Control and Prevention, Beijing, China
| | - Wentao Liu
- National Key Laboratory of Intelligent Tracking and Forecasting for Infectious Diseases, National Institute for Communicable Disease Control and Prevention, Chinese Center for Disease Control and Prevention, Beijing, China
| | - Hairui Wang
- National Key Laboratory of Intelligent Tracking and Forecasting for Infectious Diseases, National Institute for Communicable Disease Control and Prevention, Chinese Center for Disease Control and Prevention, Beijing, China
| | - Jianzhong Zhang
- National Key Laboratory of Intelligent Tracking and Forecasting for Infectious Diseases, National Institute for Communicable Disease Control and Prevention, Chinese Center for Disease Control and Prevention, Beijing, China
| | - Yanan Gong
- National Key Laboratory of Intelligent Tracking and Forecasting for Infectious Diseases, National Institute for Communicable Disease Control and Prevention, Chinese Center for Disease Control and Prevention, Beijing, China
| | - Xiaohui Wang
- Department of Gastroenterology, The Sixth Medical Center, Chinese PLA General Hospital, Beijing, China
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Umar Z, Tang JW, Marshall BJ, Tay ACY, Wang L. Rapid diagnosis and precision treatment of Helicobacter pylori infection in clinical settings. Crit Rev Microbiol 2025; 51:369-398. [PMID: 38910506 DOI: 10.1080/1040841x.2024.2364194] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/28/2024] [Revised: 05/08/2024] [Accepted: 05/25/2024] [Indexed: 06/25/2024]
Abstract
Helicobacter pylori is a gram-negative bacterium that colonizes the stomach of approximately half of the worldwide population, with higher prevalence in densely populated areas like Asia, the Caribbean, Latin America, and Africa. H. pylori infections range from asymptomatic cases to potentially fatal diseases, including peptic ulcers, chronic gastritis, and stomach adenocarcinoma. The management of these conditions has become more difficult due to the rising prevalence of drug-resistant H. pylori infections, which ultimately lead to gastric cancer and mucosa-associated lymphoid tissue (MALT) lymphoma. In 1994, the International Agency for Research on Cancer (IARC) categorized H. pylori as a Group I carcinogen, contributing to approximately 780,000 cancer cases annually. Antibiotic resistance against drugs used to treat H. pylori infections ranges between 15% and 50% worldwide, with Asian countries having exceptionally high rates. This review systematically examines the impacts of H. pylori infection, the increasing prevalence of antibiotic resistance, and the urgent need for accurate diagnosis and precision treatment. The present status of precision treatment strategies and prospective approaches for eradicating infections caused by antibiotic-resistant H. pylori will also be evaluated.
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Affiliation(s)
- Zeeshan Umar
- Marshall Laboratory of Biomedical Engineering, School of Medicine, Shenzhen University, Shenzhen, Guangdong Province, China
- Laboratory Medicine, Guangdong Provincial People's Hospital (Guangdong Academy of Medical Sciences), Southern Medical University, Guangzhou, Guangdong Province, China
| | - Jia-Wei Tang
- Laboratory Medicine, Guangdong Provincial People's Hospital (Guangdong Academy of Medical Sciences), Southern Medical University, Guangzhou, Guangdong Province, China
- The Marshall Centre for Infectious Diseases Research and Training, The University of Western Australia, Crawley, Western Australia, China
| | - Barry J Marshall
- Marshall Laboratory of Biomedical Engineering, School of Medicine, Shenzhen University, Shenzhen, Guangdong Province, China
- The Marshall Centre for Infectious Diseases Research and Training, The University of Western Australia, Crawley, Western Australia, China
- Marshall International Digestive Diseases Hospital, Zhengzhou University, Zhengzhou, Henan Province, China
- Marshall Medical Research Center, Fifth Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan Province, China
| | - Alfred Chin Yen Tay
- Marshall Laboratory of Biomedical Engineering, School of Medicine, Shenzhen University, Shenzhen, Guangdong Province, China
- The Marshall Centre for Infectious Diseases Research and Training, The University of Western Australia, Crawley, Western Australia, China
- Marshall International Digestive Diseases Hospital, Zhengzhou University, Zhengzhou, Henan Province, China
- Marshall Medical Research Center, Fifth Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan Province, China
| | - Liang Wang
- Laboratory Medicine, Guangdong Provincial People's Hospital (Guangdong Academy of Medical Sciences), Southern Medical University, Guangzhou, Guangdong Province, China
- Division of Microbiology and Immunology, School of Biomedical Sciences, The University of Western Australia, Crawley, Western Australia, China
- Center for Precision Health, School of Medical and Health Sciences, Edith Cowan University, Joondalup, Western Australia, China
- School of Agriculture and Food Sustainability, University of Queensland, Brisbane, Queensland, Australia
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Salahi-Niri A, Nabavi-Rad A, Monaghan TM, Rokkas T, Doulberis M, Sadeghi A, Zali MR, Yamaoka Y, Tacconelli E, Yadegar A. Global prevalence of Helicobacter pylori antibiotic resistance among children in the world health organization regions between 2000 and 2023: a systematic review and meta-analysis. BMC Med 2024; 22:598. [PMID: 39710669 DOI: 10.1186/s12916-024-03816-y] [Citation(s) in RCA: 1] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/06/2024] [Accepted: 12/11/2024] [Indexed: 12/24/2024] Open
Abstract
BACKGROUND Helicobacter pylori infection causes gastritis, peptic ulcers, and gastric cancer. The infection is typically acquired in childhood and persists throughout life. The major impediment to successful therapy is antibiotic resistance. This systematic review and meta-analysis aimed to comprehensively assess the global prevalence of antibiotic resistance in pediatric H. pylori infection. METHODS We performed a systematic search of publication databases that assessed H. pylori resistance rates to clarithromycin, metronidazole, levofloxacin, amoxicillin, and tetracycline in children. The WHO region classification was used to group pooled primary and secondary resistance estimates along with 95% confidence interval (CI). H. pylori antibiotic resistance rates were retrieved and combined with odds ratios (95% CI) to investigate the global prevalence and temporal trends. Subgroup analysis of the prevalence of antibiotic resistance was conducted by country, age groups, and susceptibility testing methods. RESULTS Among 1417 records obtained initially, 152 studies were selected for eligibility assessment after applying exclusion criteria in multiple steps. Ultimately, 63 studies involving 15,953 individuals were included comprising data from 28 countries in 5 WHO regions. The primary resistance rates were metronidazole 35.3% (5482/15,529, 95% CI: 28.7-42.6), clarithromycin 32.6% (5071/15,555, 95% CI: 27.7-37.9), tetracycline 2.1% (148/7033, 95% CI: 1.3-3.6), levofloxacin 13.2% (1091/8271, 95% CI: 9.3-18.4), and amoxicillin 4.8% (495/10305, 95% CI: 2.5-8.8). Raising antibiotic resistance was detected in most WHO regions. CONCLUSIONS The escalating trend of H. pylori antibiotic resistance in children warrants urgent attention globally. National and regional surveillance networks are required for antibiotic stewardship in children infected with H. pylori.
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Affiliation(s)
- Aryan Salahi-Niri
- Foodborne and Waterborne Diseases Research Center, Research Institute for Gastroenterology and Liver Diseases, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Ali Nabavi-Rad
- Foodborne and Waterborne Diseases Research Center, Research Institute for Gastroenterology and Liver Diseases, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Tanya Marie Monaghan
- National Institute for Health Research Nottingham Biomedical Research Centre, University of Nottingham, Nottingham, UK
- Nottingham Digestive Diseases Centre, School of Medicine, University of Nottingham, Nottingham, UK
| | - Theodore Rokkas
- Gastroenterology Clinic, Henry Dunant Hospital, Athens, Greece
- Medical School, European University of Cyprus, Nicosia, Cyprus
| | - Michael Doulberis
- Gastroklinik, Private Gastroenterological Practice, Horgen, 8810, Switzerland
- Division of Gastroenterology and Hepatology, Medical University Department, Kantonsspital Aarau, Aarau, 5001, Switzerland
| | - Amir Sadeghi
- Gastroenterology and Liver Diseases Research Center, Research Institute for Gastroenterology and Liver Diseases, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Mohammad Reza Zali
- Gastroenterology and Liver Diseases Research Center, Research Institute for Gastroenterology and Liver Diseases, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Yoshio Yamaoka
- Department of Environmental and Preventive Medicine, Faculty of Medicine, Oita University, Oita, Japan
- Department of Medicine, Gastroenterology and Hepatology Section, Baylor College of Medicine, Houston, TX, USA
- Research Center for Global and Local Infectious Diseases, Oita University, Oita, Japan
| | - Evelina Tacconelli
- Division of Infectious Diseases, Department of Diagnostics and Public Health, University of Verona, Verona, Italy
| | - Abbas Yadegar
- Foodborne and Waterborne Diseases Research Center, Research Institute for Gastroenterology and Liver Diseases, Shahid Beheshti University of Medical Sciences, Tehran, Iran.
- Basic and Molecular Epidemiology of Gastrointestinal Disorders Research Center, Research Institute for Gastroenterology and Liver Diseases, Shahid Beheshti University of Medical Sciences, Tehran, Iran.
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Elbehiry A, Abalkhail A, Anajirih N, Alkhamisi F, Aldamegh M, Alramzi A, AlShaqi R, Alotaibi N, Aljuaid A, Alzahrani H, Alzaben F, Rawway M, Ibrahem M, Abdelsalam MH, Rizk NI, Mostafa MEA, Alfaqir MR, Edrees HM, Alqahtani M. Helicobacter pylori: Routes of Infection, Antimicrobial Resistance, and Alternative Therapies as a Means to Develop Infection Control. Diseases 2024; 12:311. [PMID: 39727641 PMCID: PMC11727528 DOI: 10.3390/diseases12120311] [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: 10/14/2024] [Revised: 11/16/2024] [Accepted: 11/19/2024] [Indexed: 12/28/2024] Open
Abstract
Helicobacter pylori (H. pylori) is a Gram-negative, spiral-shaped bacterium that colonizes the gastric epithelium and is associated with a range of gastrointestinal disorders, exhibiting a global prevalence of approximately 50%. Despite the availability of treatment options, H. pylori frequently reemerges and demonstrates increasing antibiotic resistance, which diminishes the efficacy of conventional therapies. Consequently, it is imperative to explore non-antibiotic treatment alternatives to mitigate the inappropriate use of antibiotics. This review examines H. pylori infection, encompassing transmission pathways, treatment modalities, antibiotic resistance, and eradication strategies. Additionally, it discusses alternative therapeutic approaches such as probiotics, anti-biofilm agents, phytotherapy, phototherapy, phage therapy, lactoferrin therapy, and vaccine development. These strategies aim to reduce antimicrobial resistance and enhance treatment outcomes for H. pylori infections. While alternative therapies can maintain low bacterial levels, they do not achieve complete eradication of H. pylori. These therapies are designed to bolster the immune response, minimize side effects, and provide gastroprotective benefits, rendering them suitable for adjunctive use alongside conventional treatments. Probiotics may serve as adjunctive therapy for H. pylori; however, their effectiveness as a monotherapy is limited. Photodynamic and phage therapies exhibit potential in targeting H. pylori infections, including those caused by drug-resistant strains, without the use of antibiotics. The development of a reliable vaccine is also critical for the eradication of H. pylori. This review identifies candidate antigens such as VacA, CagA, and HspA, along with various vaccine formulations, including vector-based and subunit vaccines. Some vaccines have demonstrated efficacy in clinical trials, while others have shown robust immune protection in preclinical studies. Nevertheless, each of the aforementioned alternative therapies requires thorough preclinical and clinical evaluation to ascertain their efficacy, side effects, cost-effectiveness, and patient compliance.
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Affiliation(s)
- Ayman Elbehiry
- Department of Public Health, College of Applied Medical Sciences, Qassim University, P.O. Box 6666, Buraydah 51452, Saudi Arabia
| | - Adil Abalkhail
- Department of Public Health, College of Applied Medical Sciences, Qassim University, P.O. Box 6666, Buraydah 51452, Saudi Arabia
| | - Nuha Anajirih
- Medical Emergency Services Department, Faculty of Health Sciences, Umm Al-Qura University, Al-Qunfudah P.O. Box 1109, Saudi Arabia
| | - Fahad Alkhamisi
- Department of Preventive Medicine, King Fahad Armed Hospital, Jeddah 23311, Saudi Arabia
| | - Mohammed Aldamegh
- Pathology and Laboratory Medicine Department, Armed Forces Hospital-Jubail, Jubail 31951, Saudi Arabia
| | - Abdullah Alramzi
- Medical Radiology Department, Armed Forces Hospital-Jubail, Jubail 31951, Saudi Arabia
| | - Riyad AlShaqi
- Biomedical Engineer, Armed Forces Medical Services, Riyadh 12426, Saudi Arabia
| | - Naif Alotaibi
- Medical Hospital Administration Department, Armed Forces Hospital-Jubail, Jubail 31951, Saudi Arabia
| | - Abdullah Aljuaid
- Medical Hospital Administration Department, Armed Forces Hospitals in Al Kharj, AL Kharj 16278, Saudi Arabia
| | - Hilal Alzahrani
- Physical Medicine and Rehabilitation Department, Armed Forces Center for Health Rehabilitation, Taif 21944, Saudi Arabia
| | - Feras Alzaben
- Department of Food Service, King Fahad Armed Forces Hospital, Jeddah 23311, Saudi Arabia
| | - Mohammed Rawway
- Biology Department, College of Science, Jouf University, Sakaka 42421, Saudi Arabia
- Botany and Microbiology Department, Faculty of Science, Al-Azhar University, Assiut 71524, Egypt
| | - Mai Ibrahem
- Department of Public Health, College of Applied Medical Science, King Khalid University, Abha 61421, Saudi Arabia
| | - Moustafa H. Abdelsalam
- Department of Physiology, Faculty of Medicine, University of Tabuk, Tabuk 74191, Saudi Arabia
| | - Nermin I. Rizk
- Department of Physiology, Faculty of Medicine, University of Tabuk, Tabuk 74191, Saudi Arabia
| | - Mohamed E. A. Mostafa
- Department of Anatomy, Faculty of Medicine, University of Tabuk, Tabuk 74191, Saudi Arabia
| | - Moneef Rohail Alfaqir
- Department of Anatomy, Faculty of Medicine, University of Tabuk, Tabuk 74191, Saudi Arabia
| | - Husam M. Edrees
- Department of Physiology, Faculty of Medicine, University of Tabuk, Tabuk 74191, Saudi Arabia
| | - Mubarak Alqahtani
- Department of Radiology, King Fahd Armed Forces Hospital, Jeddah 23311, Saudi Arabia
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Krzyżek P. Helicobacter pylori Efflux Pumps: A Double-Edged Sword in Antibiotic Resistance and Biofilm Formation. Int J Mol Sci 2024; 25:12222. [PMID: 39596287 PMCID: PMC11594842 DOI: 10.3390/ijms252212222] [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: 10/28/2024] [Revised: 11/11/2024] [Accepted: 11/12/2024] [Indexed: 11/28/2024] Open
Abstract
Helicobacter pylori is a major pathogen associated with various gastric diseases. Despite decades of research, the treatment of H. pylori remains challenging. One of the primary mechanisms contributing to failures of therapies targeting this bacterium is genetic mutations in drug target sites, although the growing body of scientific data highlights that efflux pumps may also take part in this process. Efflux pumps are proteinaceous transporters actively expelling antimicrobial agents from the interior of the targeted cells and reducing the intracellular concentration of these compounds. Considering that efflux pumps contribute to both antimicrobial resistance and biofilm formation, an in-depth understanding of their properties may constitute a cornerstone in the development of novel therapeutics against H. pylori. In line with this, the aim of the current review is to describe the multitude of efflux pumps produced by H. pylori and present the data describing the involvement of these proteins in tolerance and/or resistance to various classes of antimicrobial substances.
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Affiliation(s)
- Paweł Krzyżek
- Department of Microbiology, Faculty of Medicine, Wroclaw Medical University, 50-368 Wroclaw, Poland
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Kekic D, Jovicevic M, Kabic J, Lolic I, Gajic I, Stojkovic S, Ranin L, Milosavljevic T, Opavski N, Rankovic I, Milivojevic V. Genetic Determinants of Clarithromycin and Fluoroquinolones Resistance in Helicobacter pylori in Serbia. Antibiotics (Basel) 2024; 13:933. [PMID: 39452199 PMCID: PMC11505191 DOI: 10.3390/antibiotics13100933] [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: 08/14/2024] [Revised: 09/20/2024] [Accepted: 09/29/2024] [Indexed: 10/26/2024] Open
Abstract
BACKGROUND/OBJECTIVES Stomach infections by Helicobacter pylori can cause acute or chronic gastritis, peptic ulcers, and gastric cancer. The rise in antibiotic resistance is a significant health issue highlighted by the World Health Organization. The increasing number of treatment failures underscores the necessity for antibiotic susceptibility testing (AST). The study aimed to investigate the current prevalence and resistance to fluoroquinolones and clarithromycin with their detected mutations. METHODS Stomach biopsies from symptomatic patients were subjected to molecular testing by GenoType Helico DR kit (Hain Lifescience GmbH, Nehren, Germany). RESULTS Positive findings on the presence of H. pylori were detected in 42.4% of symptomatic patients, with the significant majority of patients (69%) having previously failed treatments. The resistance rates to fluoroquinolones and clarithromycin were 53.9% and 58.5%, respectively, with significantly higher rates in secondary resistant strains. The main resistance markers in fluoroquinolones and clarithromycin were N87K (27.4%) and A2147G (78.6%), respectively. Hetero-resistance or mixed genotypes were detected in over 20% of tested patients. During the study period, a significant increase in trends in both fluoroquinolones and clarithromycin resistance rates was observed. CONCLUSIONS Results indicate the need for the implementation of the latest Maastricht VI Consensus recommendations for both AST whenever possible and the use of tailored guided therapy options due to high resistance rates and possible treatment failures. The GenoType Helico DR kit is a useful tool for AST, especially in cases of mixed H. pylori genotypes.
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Affiliation(s)
- Dusan Kekic
- Institute for Microbiology and Immunology, Faculty of Medicine, University of Belgrade, 11 000 Belgrade, Serbia
| | - Milos Jovicevic
- Institute for Microbiology and Immunology, Faculty of Medicine, University of Belgrade, 11 000 Belgrade, Serbia
| | - Jovana Kabic
- Institute for Microbiology and Immunology, Faculty of Medicine, University of Belgrade, 11 000 Belgrade, Serbia
| | - Iva Lolic
- Emergency Center, University Clinical Center of Serbia, 11 000 Belgrade, Serbia
| | - Ina Gajic
- Institute for Microbiology and Immunology, Faculty of Medicine, University of Belgrade, 11 000 Belgrade, Serbia
| | - Stefan Stojkovic
- Clinic for Gastroenterology and Hepatology, University Clinical Centre of Serbia, 11 000 Belgrade, Serbia
| | - Lazar Ranin
- Institute for Microbiology and Immunology, Faculty of Medicine, University of Belgrade, 11 000 Belgrade, Serbia
| | | | - Natasa Opavski
- Institute for Microbiology and Immunology, Faculty of Medicine, University of Belgrade, 11 000 Belgrade, Serbia
| | - Ivan Rankovic
- Department of Gastroenterology and Liver Care, Royal Cornwall Hospitals NHS Trust University of Exeter, Treliske, Truro, Cornwall TR1 3LQ, UK
| | - Vladimir Milivojevic
- Clinic for Gastroenterology and Hepatology, University Clinical Centre of Serbia, 11 000 Belgrade, Serbia
- Faculty of Medicine, University of Belgrade, 11 000 Belgrade, Serbia
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Ng HK, Chua KH, Kee BP, Chuah KH, Por LY, Puah SM. Genetic variations of penicillin-binding protein 1A: insights into the current status of amoxicillin-based regimens for Helicobacter pylori eradication in Malaysia. J Med Microbiol 2024; 73. [PMID: 38712922 DOI: 10.1099/jmm.0.001832] [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] [Indexed: 05/08/2024] Open
Abstract
Introduction. Resistance towards amoxicillin in Helicobacter pylori causes significant therapeutic impasse in healthcare settings worldwide. In Malaysia, the standard H. pylori treatment regimen includes a 14-day course of high-dose proton-pump inhibitor (rabeprazole, 20 mg) with amoxicillin (1000 mg) dual therapy.Hypothesis/Gap Statement. The high eradication rate with amoxicillin-based treatment could be attributed to the primary resistance rates of amoxicillin being relatively low at 0%, however, a low rate of secondary resistance has been documented in Malaysia recently.Aim. This study aims to investigate the amino acid mutations and related genetic variants in PBP1A of H. pylori, correlating with amoxicillin resistance in the Malaysian population.Methodology. The full-length pbp1A gene was amplified via PCR from 50 genomic DNA extracted from gastric biopsy samples of H. pylori-positive treatment-naïve Malaysian patients. The sequences were then compared with reference H. pylori strain ATCC 26695 for mutation and variant detection. A phylogenetic analysis of 50 sequences along with 43 additional sequences from the NCBI database was performed. These additional sequences included both amoxicillin-resistant strains (n=20) and amoxicillin-sensitive strains (n=23).Results. There was a total of 21 variants of amino acids, with three of them located in or near the PBP-motif (SKN402-404). The percentages of these three variants are as follows: K403X, 2%; S405I, 2% and E406K, 16%. Based on the genetic markers identified, the resistance rate for amoxicillin in our sample remained at 0%. The phylogenetic examination suggested that H. pylori might exhibit unique conserved pbp1A sequences within the Malaysian context.Conclusions. Overall, the molecular analysis of PBP1A supported the therapeutic superiority of amoxicillin-based regimens. Therefore, it is crucial to continue monitoring the amoxicillin resistance background of H. pylori with a larger sample size to ensure the sustained effectiveness of amoxicillin-based treatments in Malaysia.
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Affiliation(s)
- Heng Kang Ng
- Department of Biomedical Science, Faculty of Medicine, Universiti Malaya, 50603 Kuala Lumpur, Malaysia
| | - Kek Heng Chua
- Department of Biomedical Science, Faculty of Medicine, Universiti Malaya, 50603 Kuala Lumpur, Malaysia
| | - Boon Pin Kee
- Department of Biomedical Science, Faculty of Medicine, Universiti Malaya, 50603 Kuala Lumpur, Malaysia
| | - Kee Huat Chuah
- Department of Medicine, Faculty of Medicine, Universiti Malaya, 50603 Kuala Lumpur, Malaysia
| | - Lip Yee Por
- Department of Computer System and Technology, Faculty of Computer Science and Information Technology, Universiti Malaya, 50603 Kuala Lumpur, Malaysia
| | - Suat Moi Puah
- Department of Biomedical Science, Faculty of Medicine, Universiti Malaya, 50603 Kuala Lumpur, Malaysia
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Rosli NA, Al-Maleki AR, Loke MF, Chua EG, Alhoot MA, Vadivelu J. Polymorphism of virulence genes and biofilm associated with in vitro induced resistance to clarithromycin in Helicobacter pylori. Gut Pathog 2023; 15:52. [PMID: 37898785 PMCID: PMC10613384 DOI: 10.1186/s13099-023-00579-4] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/02/2023] [Accepted: 10/19/2023] [Indexed: 10/30/2023] Open
Abstract
BACKGROUND Clarithromycin-containing triple therapy is commonly used to treat Helicobacter pylori infections. Clarithromycin resistance is the leading cause of H. pylori treatment failure. Understanding the specific mutations that occur in H. pylori strains that have evolved antibiotic resistance can help create a more effective and individualised antibiotic treatment plan. However, little is understood about the genetic reprogramming linked to clarithromycin exposure and the emergence of antibiotic resistance in H. pylori. Therefore, this study aims to identify compensatory mutations and biofilm formation associated with the development of clarithromycin resistance in H. pylori. Clarithromycin-sensitive H. pylori clinical isolates were induced to develop clarithromycin resistance through in vitro exposure to incrementally increasing concentration of the antibiotic. The genomes of the origin sensitive isolates (S), isogenic breakpoint (B), and resistant isolates (R) were sequenced. Single nucleotide variations (SNVs), and insertions or deletions (InDels) associated with the development of clarithromycin resistance were identified. Growth and biofilm production were also assessed. RESULTS The S isolates with A2143G mutation in the 23S rRNA gene were successfully induced to be resistant. According to the data, antibiotic exposure may alter the expression of certain genes, including those that code for the Cag4/Cag protein, the vacuolating cytotoxin domain-containing protein, the sel1 repeat family protein, and the rsmh gene, which may increase the risk of developing and enhances virulence in H. pylori. Enhanced biofilm formation was detected among R isolates compared to B and S isolates. Furthermore, high polymorphism was also detected among the genes associated with biofilm production. CONCLUSIONS Therefore, this study suggests that H. pylori may acquire virulence factors while also developing antibiotic resistance due to clarithromycin exposure.
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Affiliation(s)
- Naim Asyraf Rosli
- Department of Medical Microbiology, Faculty of Medicine, Universiti Malaya, 50603, Kuala Lumpur, Malaysia
| | - Anis Rageh Al-Maleki
- Department of Medical Microbiology, Faculty of Medicine, Universiti Malaya, 50603, Kuala Lumpur, Malaysia.
- Department of Medical Microbiology, Faculty of Medicine and Health Sciences, Sana'a University, Sana'a, Yemen.
| | - Mun Fai Loke
- Camtech Biomedical Pte Ltd, Singapore, Singapore
| | - Eng Guan Chua
- School of Biomedical Sciences, Marshall Centre for Infectious Disease Research and Training, University of Western Australia, Perth, WA, Australia
| | - Mohammed Abdelfatah Alhoot
- Faculty of Pharmacy, Airlangga University, Surabaya, 60155, Indonesia
- School of Graduate Studies, Management & Science University, Shah Alam, Selangor, Malaysia
| | - Jamuna Vadivelu
- Medical Education Research and Development Unit, Faculty of Medicine, Universiti Malaya, Kuala Lumpur, Malaysia
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Monroy FP, Brown HE, Acevedo-Solis CM, Rodriguez-Galaviz A, Dholakia R, Pauli L, Harris RB. Antibiotic Resistance Rates for Helicobacter pylori in Rural Arizona: A Molecular-Based Study. Microorganisms 2023; 11:2290. [PMID: 37764134 PMCID: PMC10536767 DOI: 10.3390/microorganisms11092290] [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: 07/05/2023] [Revised: 08/29/2023] [Accepted: 09/06/2023] [Indexed: 09/29/2023] Open
Abstract
Helicobacter pylori (H. pylori) is a common bacterial infection linked to gastric malignancies. While H. pylori infection and gastric cancer rates are decreasing, antibiotic resistance varies greatly by community. Little is known about resistance rates among rural Indigenous populations in the United States. From 2018 to 2021, 396 endoscopy patients were recruited from a Northern Arizona clinic, where community H. pylori prevalence is near 60%. Gastric biopsy samples positive for H. pylori (n = 67) were sequenced for clarithromycin- and metronidazole-associated mutations, 23S ribosomal RNA (23S), and oxygen-insensitive NADPH nitroreductase (rdxA) regions. Medical record data were extracted for endoscopic findings and prior H. pylori history. Data analysis was restricted to individuals with no history of H. pylori infection. Of 49 individuals, representing 64 samples which amplified in the 23S region, a clarithromycin-associated mutation was present in 38.8%, with T2182C being the most common mutation at 90%. While the prevalence of metronidazole-resistance-associated mutations was higher at 93.9%, the mutations were more variable, with D95N being the most common followed by L62V. No statistically significant sex differences were observed for either antibiotic. Given the risk of treatment failure with antibiotic resistance, there is a need to consider resistance profile during treatment selection. The resistance rates in this population of American Indian patients undergoing endoscopy are similar to other high-risk populations. This is concerning given the high H. pylori prevalence and low rates of resistance testing in clinical settings. The mutations reported are associated with antibiotic resistance, but clinical resistance must be confirmed.
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Affiliation(s)
- Fernando P. Monroy
- Department of Biological Sciences, College of the Environment, Forestry and Natural Sciences, Northern Arizona University, 617 South Beaver Street, Flagstaff, AZ 86011, USA
- Pathogen and Microbiome Institute, Northern Arizona University, Flagstaff, AZ 86011, USA
| | - Heidi E. Brown
- Department of Epidemiology and Biostatistics, Mel and Enid Zuckerman College of Public Health, 1295 N Martin Ave, Tucson, AZ 85724, USA (R.B.H.)
| | - Claudia M. Acevedo-Solis
- Department of Biological Sciences, College of the Environment, Forestry and Natural Sciences, Northern Arizona University, 617 South Beaver Street, Flagstaff, AZ 86011, USA
| | - Andres Rodriguez-Galaviz
- Department of Biological Sciences, College of the Environment, Forestry and Natural Sciences, Northern Arizona University, 617 South Beaver Street, Flagstaff, AZ 86011, USA
| | - Rishi Dholakia
- Winslow Indian Health Care Center, 500 North Indiana Avenue, Winslow, AZ 86047, USA (L.P.)
| | - Laura Pauli
- Winslow Indian Health Care Center, 500 North Indiana Avenue, Winslow, AZ 86047, USA (L.P.)
| | - Robin B. Harris
- Department of Epidemiology and Biostatistics, Mel and Enid Zuckerman College of Public Health, 1295 N Martin Ave, Tucson, AZ 85724, USA (R.B.H.)
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10
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Shirani M, Pakzad R, Haddadi MH, Akrami S, Asadi A, Kazemian H, Moradi M, Kaviar VH, Zomorodi AR, Khoshnood S, Shafieian M, Tavasolian R, Heidary M, Saki M. The global prevalence of gastric cancer in Helicobacter pylori-infected individuals: a systematic review and meta-analysis. BMC Infect Dis 2023; 23:543. [PMID: 37598157 PMCID: PMC10439572 DOI: 10.1186/s12879-023-08504-5] [Citation(s) in RCA: 30] [Impact Index Per Article: 15.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/30/2022] [Accepted: 07/31/2023] [Indexed: 08/21/2023] Open
Abstract
BACKGROUND Helicobacter pylori is a gastrointestinal pathogen that infects around half of the world's population. H. pylori infection is the most severe known risk factor for gastric cancer (GC), which is the second highest cause of cancer-related deaths globally. We conducted a systematic review and meta-analysis to assess the global prevalence of GC in H. pylori-infected individuals. METHODS We performed a systematic search of the PubMed, Web of Science, and Embase databases for studies of the prevalence of GC in H. pylori-infected individuals published from 1 January 2011 to 20 April 2021. Metaprop package were used to calculate the pooled prevalence with 95% confidence interval. Random-effects model was applied to estimate the pooled prevalence. We also quantified it with the I2 index. Based on the Higgins classification approach, I2 values above 0.7 were determined as high heterogeneity. RESULTS Among 17,438 reports screened, we assessed 1053 full-text articles for eligibility; 149 were included in the final analysis, comprising data from 32 countries. The highest and lowest prevalence was observed in America (pooled prevalence: 18.06%; 95% CI: 16.48 - 19.63; I2: 98.84%) and Africa (pooled prevalence: 9.52%; 95% CI: 5.92 - 13.12; I2: 88.39%). Among individual countries, Japan had the highest pooled prevalence of GC in H. pylori positive patients (Prevalence: 90.90%:95% CI: 83.61-95.14), whereas Sweden had the lowest prevalence (Prevalence: 0.07%; 95% CI: 0.06-0.09). The highest and lowest prevalence was observed in prospective case series (pooled prevalence: 23.13%; 95% CI: 20.41 - 25.85; I2: 97.70%) and retrospective cohort (pooled prevalence: 1.17%; 95% CI: 0.55 - 1.78; I 2: 0.10%). CONCLUSIONS H. pylori infection in GC patients varied between regions in this systematic review and meta-analysis. We observed that large amounts of GCs in developed countries are associated with H. pylori. Using these data, regional initiatives can be taken to prevent and eradicate H. pylori worldwide, thus reducing its complications.
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Affiliation(s)
- Maryam Shirani
- Toxicology Research Center, Medical Basic Sciences Research Institute, Ahvaz Jundishapur University of Medical Sciences, Ahvaz, Iran
| | - Reza Pakzad
- Department of Epidemiology, Faculty of Health, Ilam University Medical Sciences, Ilam, Iran
- Student Research Committee, Ilam University of Medical Sciences, Ilam, Iran
| | | | - Sousan Akrami
- Students' Scientific Research Center (SSRC), Tehran University of Medical Sciences, Tehran, Iran
- Department of Microbiology, Faculty of Medicine, Ahvaz Jundishapur University of Medical Sciences, Ahvaz, Iran
| | - Arezoo Asadi
- Endocrine Research Center, Institute of Endocrinology and Metabolism, Iran University of Medical Sciences, Tehran, Iran
| | - Hossein Kazemian
- Clinical Microbiology Research Center, Ilam University of Medical Sciences, Ilam, Iran
| | - Melika Moradi
- Department of Microbiology, Faculty of Medicine, Ahvaz Jundishapur University of Medical Sciences, Ahvaz, Iran
| | - Vahab Hassan Kaviar
- Department of Medical Microbiology, Faculty of Medicine, Ilam University of Medical Science, Ilam, Iran
| | - Abolfazl Rafati Zomorodi
- Department of Bacteriology and Virology, School of Medicine, Shiraz University of Medical Sciences, Shiraz, Iran
| | - Saeed Khoshnood
- Student Research Committee, Ilam University of Medical Sciences, Ilam, Iran
- Clinical Microbiology Research Center, Ilam University of Medical Sciences, Ilam, Iran
| | - Mahnaz Shafieian
- Department of Midwifery, Faculty of Nursing and Midwifery, Ilam University of Medical Sciences, Ilam, Iran
| | - Ronia Tavasolian
- Department of Medicine, Faculty of Nutrition Science, University of Cheste, Chester, UK
| | - Mohsen Heidary
- Department of Laboratory Sciences, School of Paramedical Sciences, Sabzevar University of Medical Sciences, Sabzevar, Iran.
- Cellular and Molecular Research Center, Sabzevar University of Medical Sciences, Sabzevar, Iran.
| | - Morteza Saki
- Department of Microbiology, Faculty of Medicine, Ahvaz Jundishapur University of Medical Sciences, Ahvaz, Iran.
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11
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Grudlewska-Buda K, Bauza-Kaszewska J, Wiktorczyk-Kapischke N, Budzyńska A, Gospodarek-Komkowska E, Skowron K. Antibiotic Resistance in Selected Emerging Bacterial Foodborne Pathogens-An Issue of Concern? Antibiotics (Basel) 2023; 12:antibiotics12050880. [PMID: 37237783 DOI: 10.3390/antibiotics12050880] [Citation(s) in RCA: 4] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/24/2023] [Revised: 04/30/2023] [Accepted: 05/07/2023] [Indexed: 05/28/2023] Open
Abstract
Antibiotic resistance (AR) and multidrug resistance (MDR) have been confirmed for all major foodborne pathogens: Campylobacter spp., Salmonella spp., Escherichia coli and Listeria monocytogenes. Of great concern to scientists and physicians are also reports of antibiotic-resistant emerging food pathogens-microorganisms that have not previously been linked to food contamination or were considered epidemiologically insignificant. Since the properties of foodborne pathogens are not always sufficiently recognized, the consequences of the infections are often not easily predictable, and the control of their activity is difficult. The bacteria most commonly identified as emerging foodborne pathogens include Aliarcobacter spp., Aeromonas spp., Cronobacter spp., Vibrio spp., Clostridioides difficile, Escherichia coli, Mycobacterium paratuberculosis, Salmonella enterica, Streptocccus suis, Campylobacter jejuni, Helicobacter pylori, Listeria monocytogenes and Yersinia enterocolitica. The results of our analysis confirm antibiotic resistance and multidrug resistance among the mentioned species. Among the antibiotics whose effectiveness is steadily declining due to expanding resistance among bacteria isolated from food are β-lactams, sulfonamides, tetracyclines and fluoroquinolones. Continuous and thorough monitoring of strains isolated from food is necessary to characterize the existing mechanisms of resistance. In our opinion, this review shows the scale of the problem of microbes related to health, which should not be underestimated.
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Affiliation(s)
- Katarzyna Grudlewska-Buda
- Department of Microbiology, Ludwik Rydygier Collegium Medicum in Bydgoszcz, Nicolaus Copernicus University in Toruń, 85-094 Bydgoszcz, Poland
| | - Justyna Bauza-Kaszewska
- Department of Microbiology and Food Technology, Bydgoszcz University of Science and Technology, 85-029 Bydgoszcz, Poland
| | - Natalia Wiktorczyk-Kapischke
- Department of Microbiology, Ludwik Rydygier Collegium Medicum in Bydgoszcz, Nicolaus Copernicus University in Toruń, 85-094 Bydgoszcz, Poland
| | - Anna Budzyńska
- Department of Microbiology, Ludwik Rydygier Collegium Medicum in Bydgoszcz, Nicolaus Copernicus University in Toruń, 85-094 Bydgoszcz, Poland
| | - Eugenia Gospodarek-Komkowska
- Department of Microbiology, Ludwik Rydygier Collegium Medicum in Bydgoszcz, Nicolaus Copernicus University in Toruń, 85-094 Bydgoszcz, Poland
| | - Krzysztof Skowron
- Department of Microbiology, Ludwik Rydygier Collegium Medicum in Bydgoszcz, Nicolaus Copernicus University in Toruń, 85-094 Bydgoszcz, Poland
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12
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Matta AJ, Zambrano DC, Martínez YC, Fernández FF. Point mutations in the glycosyltransferase domain of the pbp1a gene in amoxicillin-resistant Helicobacter pylori isolates. REVISTA DE GASTROENTEROLOGIA DE MEXICO (ENGLISH) 2023; 88:100-106. [PMID: 35661638 DOI: 10.1016/j.rgmxen.2021.05.015] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 08/09/2020] [Accepted: 05/14/2021] [Indexed: 02/07/2023]
Abstract
INTRODUCTION Helicobacter pylori (H. pylori) eradication treatment includes a proton pump inhibitor and two antibiotics: amoxicillin and clarithromycin. The goal of that treatment is to eradicate the infection in at least 90% of the patients. Failure to eradicate the infection can have multiple causes, among which is the presence of point mutations in the antimicrobial target genes. OBJECTIVE To characterize the mutations present in the pbp1a gene and their possible association with resistance to amoxicillin in vitro. METHODOLOGY Susceptibility to amoxicillin was evaluated in 147 isolates of H. pylori from the Colombian municipality of Túquerres. PCR amplification and sequencing of the glycosyltransferase domain of the pbp1a gene were carried out on Túquerres isolates, and the association between mutations and resistance was evaluated. RESULTS A total of 5.4% (8/147) Túquerres isolates were resistant to amoxicillin in vitro. PCR amplification of the glycosyltransferase domain of the pbp1A gene was performed on 87.5% of the amoxicillin-resistant isolates in vitro, and in the DNA sequencing analysis, a total of 2 changes of amino acids from 3 DNA mutations that encoded the PBP1A-1 protein were observed. CONCLUSION The present study is the first report on pbp1a gene mutations in H. pylori isolates coming from a population in Túquerres. Mutations that have not been reported in previous studies were found.
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Affiliation(s)
- A J Matta
- Facultad de Ciencias de la Educación y el Deporte, Escuela Nacional del Deporte, Cali, Colombia
| | - D C Zambrano
- Facultad de Ciencias de la Educación y el Deporte, Escuela Nacional del Deporte, Cali, Colombia
| | - Y C Martínez
- Facultad de Salud, Escuela de Medicina, Corporación Universitaria Rafael Núñez, Cartagena de Indias, Colombia
| | - F F Fernández
- Facultad de Ciencias, Universidad San Buenaventura, Cali, Colombia.
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Sholeh M, Khoshnood S, Azimi T, Mohamadi J, Kaviar VH, Hashemian M, Karamollahi S, Sadeghifard N, Heidarizadeh H, Heidary M, Saki M. The prevalence of clarithromycin-resistant Helicobacter pylori isolates: a systematic review and meta-analysis. PeerJ 2023; 11:e15121. [PMID: 37016679 PMCID: PMC10066884 DOI: 10.7717/peerj.15121] [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: 01/03/2023] [Accepted: 03/03/2023] [Indexed: 04/06/2023] Open
Abstract
BACKGROUND Knowledge of global clarithromycin (CLA)-resistant rates of Helicobacter pylori (H. pylori) is crucial for decision of the most appropriate eradication therapies with good clinical outcomes. Therefore, this review and meta-analysis aimed to evaluate the global prevalence of the CLA resistance in H. pylori to provide some guidance for selecting the first-line antibiotics. METHOD A comprehensive search was performed for relevant literature until April 2021 in PubMed, Embase, and Web of Science databases. Freeman-Tukey double arcsine transformation was performed to estimate the weighted pooled prevalence of resistance. RESULTS The meta-analysis included 248 articles. The prevalence of CLA-resistant H. pylori was 27.53% (95% CI [25.41-29.69]). The heterogeneity between reports was significant (I2 = 97.80%, P < 0.01). The resistance rate increased from 24.28% in 2010-2017 to 32.14% in 2018-2021 (P < 0.01). Iran, with 38 articles, has the most report. Nevertheless, Switzerland, Portugal, and Israel had the highest resistance rates (67.16%, 48.11%, and 46.12%, respectively). The heterogeneity between the continents and the antimicrobial susceptibility methods also interpreted standard guidelines and breakpoints was insignificant (P > 0.05). CONCLUSION Overall CLA resistance rate was 27.53%, worldwide. The difference in CLA resistance rate among the included studies can be due to several reasons such as differences in antibiotic prescription rates in various geographic areas, use of different breakpoints or inaccurate criteria in performed studies, and the emergence of multidrug-resistant (MDR) strains.
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Affiliation(s)
- Mohammad Sholeh
- Department of Microbiology, Pasteur Institute of Iran, Tehran, Iran
| | - Saeed Khoshnood
- Clinical Microbiology Research Center, Ilam University of Medical Sciences, Ilam, Iran
- Student Research Committee, Ilam University of Medical Sciences, Ilam, Iran
| | - Taher Azimi
- Department of Bacteriology and Virology, School of Medicine, Shiraz University of Medical Sciences, Shiraz, Iran
| | - Jasem Mohamadi
- Department of Pediatrics, School of Medicine, Emam Khomeini Hospital, Ilam University of Medical Sciences, Ilam, Iran
| | - Vahab Hassan Kaviar
- Clinical Microbiology Research Center, Ilam University of Medical Sciences, Ilam, Iran
| | - Marzieh Hashemian
- Department of Microbiology, School of Medicine, Ilam University of Medical Sciences, Ilam, Iran
| | - Somayeh Karamollahi
- Department of Microbiology, School of Medicine, Ilam University of Medical Sciences, Ilam, Iran
| | - Nourkhoda Sadeghifard
- Clinical Microbiology Research Center, Ilam University of Medical Sciences, Ilam, Iran
| | - Hedayat Heidarizadeh
- Department of Pediatrics, School of Medicine, Emam Khomeini Hospital, Ilam University of Medical Sciences, Ilam, Iran
| | - Mohsen Heidary
- Department of Laboratory Sciences, School of Paramedical Sciences, Sabzevar University of Medical Sciences, Sabzevar, Iran
- Cellular and Molecular Research Center, Sabzevar University of Medical Sciences, Sabzevar, Iran
| | - Morteza Saki
- Department of Microbiology, Faculty of Medicine, Ahvaz Jundishapur University of Medical Sciences, Ahvaz, Iran
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Srisuphanunt M, Wilairatana P, Kooltheat N, Duangchan T, Katzenmeier G, Rose JB. Molecular Mechanisms of Antibiotic Resistance and Novel Treatment Strategies for Helicobacter pylori Infections. Trop Med Infect Dis 2023; 8:163. [PMID: 36977164 PMCID: PMC10057134 DOI: 10.3390/tropicalmed8030163] [Citation(s) in RCA: 19] [Impact Index Per Article: 9.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/24/2022] [Revised: 03/06/2023] [Accepted: 03/06/2023] [Indexed: 03/18/2023] Open
Abstract
Helicobacter pylori infects approximately 50% of the world's population and is considered the major etiological agent of severe gastric diseases, such as peptic ulcers and gastric carcinoma. Increasing resistance to standard antibiotics has now led to an ever-decreasing efficacy of eradication therapies and the development of novel and improved regimens for treatment is urgently required. Substantial progress has been made over the past few years in the identification of molecular mechanisms which are conducive to resistant phenotypes as well as for efficient strategies to counteract strain resistance and to avoid the use of ineffective antibiotics. These involve molecular testing methods, improved salvage therapies, and the discovery of novel and potent antimicrobial compounds. High rates of prevalence and gastric cancer are currently observed in Asian countries, including Japan, China, Korea, and Taiwan, where concomitantly intensive research efforts were initiated to explore advanced eradication regimens aimed at reducing the risk of gastric cancer. In this review, we present an overview of the known molecular mechanisms of antibiotic resistance and discuss recent intervention strategies for H. pylori diseases, with a view of the research progress in Asian countries.
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Affiliation(s)
- Mayuna Srisuphanunt
- Department of Medical Technology, School of Allied Health Sciences, Walailak University, Nakhon Si Thammarat 80160, Thailand
- Excellent Center for Dengue and Community Public Health, School of Public Health, Walailak University, Nakhon Si Thammarat 80160, Thailand
| | - Polrat Wilairatana
- Department of Clinical Tropical Medicine, Faculty of Tropical Medicine, Mahidol University, Bangkok 10400, Thailand
| | - Nateelak Kooltheat
- Department of Medical Technology, School of Allied Health Sciences, Walailak University, Nakhon Si Thammarat 80160, Thailand
- Hematology and Transfusion Science Research Center, School of Allied Health Sciences, Walailak University, Nakhon Si Thammarat 80160, Thailand
| | - Thitinat Duangchan
- Department of Medical Technology, School of Allied Health Sciences, Walailak University, Nakhon Si Thammarat 80160, Thailand
- Hematology and Transfusion Science Research Center, School of Allied Health Sciences, Walailak University, Nakhon Si Thammarat 80160, Thailand
| | - Gerd Katzenmeier
- Akkhraratchakumari Veterinary College, Walailak University, Nakhon Si Thammarat 80160, Thailand
| | - Joan B. Rose
- Department of Fisheries and Wildlife, Michigan State University, East Lansing, MI 48823, USA
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15
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Boyanova L, Hadzhiyski P, Gergova R, Markovska R. Evolution of Helicobacter pylori Resistance to Antibiotics: A Topic of Increasing Concern. Antibiotics (Basel) 2023; 12:antibiotics12020332. [PMID: 36830243 PMCID: PMC9952372 DOI: 10.3390/antibiotics12020332] [Citation(s) in RCA: 57] [Impact Index Per Article: 28.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/10/2023] [Revised: 01/31/2023] [Accepted: 02/01/2023] [Indexed: 02/09/2023] Open
Abstract
Antibiotic resistance among Helicobacter pylori strains is the major cause of eradication failure. Resistance prevalence is dynamic and can greatly vary among countries over the years. We revealed H. pylori resistance trends for five antibiotics in 14 countries through articles predominantly published in 2018-2022, since the latest data can best show the most recent trends in resistance evolution. Amoxicillin resistance generally exhibited no evolution, yet it increased in Bulgaria, Iran, China, and Vietnam. Metronidazole resistance exhibited different trends, including an increase, a decrease and no evolution in six, three, and five studies, respectively. Clarithromycin resistance increased in Australia, Belgium, Bulgaria, Italy, Iran, and Taiwan, but remained stable in France, Spain, Russia, China, Chile, and Colombia. Tetracycline resistance was low and stable except in Iran. Levofloxacin resistance increased in four European and six other countries/regions, without significant increases in France, Spain, and Chile. In Chile, triple resistance also increased. In countries such as France and Spain, resistance to most antibiotics was stabilized, while in Bulgaria, Belgium, Iran and Taiwan, resistance to three or more agents was reported. Use of non-recommended regimens, national antibiotic consumption, patient's compliance, host factors, strain virulence, migrations, and azithromycin overuse during the COVID-19 pandemic can influence resistance evolution. New drugs, eradication regimens and diagnostic methods, such as next-generation sequencing can improve H. pylori infection control.
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Affiliation(s)
- Lyudmila Boyanova
- Department of Medical Microbiology, Medical Faculty, Medical University of Sofia, Zdrave str. 2, 1431 Sofia, Bulgaria
- Correspondence: ; Tel.: +359-2-91-72-730
| | - Petyo Hadzhiyski
- Specialized Hospital for Active Pediatric Treatment, Medical University of Sofia, “Acad. Ivan Evstatiev Geshov” blvd., 1606 Sofia, Bulgaria
| | - Raina Gergova
- Department of Medical Microbiology, Medical Faculty, Medical University of Sofia, Zdrave str. 2, 1431 Sofia, Bulgaria
| | - Rumyana Markovska
- Department of Medical Microbiology, Medical Faculty, Medical University of Sofia, Zdrave str. 2, 1431 Sofia, Bulgaria
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Quebral EPB, Badua CLD, Tantengco OAG. Helicobacter pylori infection and the risk of gastric cancer in the Philippines. THE LANCET REGIONAL HEALTH. WESTERN PACIFIC 2022; 23:100475. [PMID: 35542893 PMCID: PMC9079792 DOI: 10.1016/j.lanwpc.2022.100475] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Download PDF] [Subscribe] [Scholar Register] [Indexed: 06/14/2023]
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17
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Lormohammadi L, Nikkhahi F, Bolori S, Karami AA, Hajian S, Rad N, Peymani A, Samimi R. High level of resistance to metronidazole and clarithromycin among Helicobacter pylori clinical isolates in Qazvin province, Iran. GENE REPORTS 2022. [DOI: 10.1016/j.genrep.2022.101494] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/07/2023]
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18
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Isolation of dupA-positive and clarithromycin-resistant Helicobacter pylori from Iranian patients with duodenal ulcer. GENE REPORTS 2021. [DOI: 10.1016/j.genrep.2021.101228] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/24/2022]
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Shaulov Y, Sarid L, Trebicz-Geffen M, Ankri S. Entamoeba histolytica Adaption to Auranofin: A Phenotypic and Multi-Omics Characterization. Antioxidants (Basel) 2021; 10:antiox10081240. [PMID: 34439488 PMCID: PMC8389260 DOI: 10.3390/antiox10081240] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/21/2021] [Revised: 07/25/2021] [Accepted: 07/30/2021] [Indexed: 12/01/2022] Open
Abstract
Auranofin (AF), an antirheumatic agent, targets mammalian thioredoxin reductase (TrxR), an important enzyme controlling redox homeostasis. AF is also highly effective against a diversity of pathogenic bacteria and protozoan parasites. Here, we report on the resistance of the parasite Entamoeba histolytica to 2 µM of AF that was acquired by gradual exposure of the parasite to an increasing amount of the drug. AF-adapted E. histolytica trophozoites (AFAT) have impaired growth and cytopathic activity, and are more sensitive to oxidative stress (OS), nitrosative stress (NS), and metronidazole (MNZ) than wild type (WT) trophozoites. Integrated transcriptomics and redoxomics analyses showed that many upregulated genes in AFAT, including genes encoding for dehydrogenase and cytoskeletal proteins, have their product oxidized in wild type trophozoites exposed to AF (acute AF trophozoites) but not in AFAT. We also showed that the level of reactive oxygen species (ROS) and oxidized proteins (OXs) in AFAT is lower than that in acute AF trophozoites. Overexpression of E. histolytica TrxR (EhTrxR) did not protect the parasite against AF, which suggests that EhTrxR is not central to the mechanism of adaptation to AF.
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Ye SF, Zhang JM, Dai F, Lan CJ, Zhang XJ, Zhou LZ, Tang QQ, Meng F. Investigation of mutation of multidrug resistant Helicobacter pylori efflux pump gene based on whole genome sequencing. Shijie Huaren Xiaohua Zazhi 2021; 29:455-460. [DOI: 10.11569/wcjd.v29.i9.455] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/06/2023] Open
Abstract
BACKGROUND More than 50% of the world's population are infected with Helicobacter pylori (H. pylori). With the widespread use of antibiotics, antibiotic resistance has become the main reason for the failure of H. pylori eradication. At present, many studies have reported that the overexpression of efflux pump genes is related to the development of drug resistance.
AIM To explore the internal connection between the mutation of efflux pump gene and the resistance of double drug resistant strains.
METHODS 13C-breath test and drug susceptibility test were used to screen double drug resistant strains and sensitive strains, and conventional methods of specific PCR were used to verify the mutation sites of drug resistance related genes. Based on the MiSeq platform, the whole genome sequence of ten clinical strains was performed. The single nucleotide variants (SNV) of the efflux pump gene of the double drug resistant phenotype and the sensitive phenotype were then identified and analyzed. The reference strain was ATCC26695.
RESULTS The results of the H. pylori susceptibility test showed that H. pylori in Lishui area had a high resistance rate to clarithromycin and levofloxacin. Specific PCR detected 23S rRNA gene and gyrA point mutations in five clinically double drug resistant strains, but not in the five clinically sensitive strains. Whole genome sequencing detected the genetic variation of four gene clusters (HP0605-HP0607, HP0971-HP0969, HP1327-HP1329, and HP1489-HP1487) involved in multi-drug resistance TolC homologs. A mutant SNV was found in double drug resistant H. pylori strains.
CONCLUSION The use of antibiotics in Lishui area should be strictly monitored to avoid abuse. The gene cluster of TolC homologous genes is related to the antibiotic resistance of H. pylori strains. Whole genome sequencing can help provide a new understanding of the relationship between genotype and phenotype.
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Affiliation(s)
- Shu-Fang Ye
- Department of Gastroenterology, Lishui City People's Hospital, Lishui 323000, Zhejiang Province, China
| | - Jian-Mei Zhang
- Department of Gastroenterology, Lishui City People's Hospital, Lishui 323000, Zhejiang Province, China
| | - Fei Dai
- Department of Gastroenterology, Lishui City People's Hospital, Lishui 323000, Zhejiang Province, China
| | - Chen-Ju Lan
- Department of Gastroenterology, Lishui City People's Hospital, Lishui 323000, Zhejiang Province, China
| | - Xiao-Jun Zhang
- Department of Gastroenterology, Lishui City People's Hospital, Lishui 323000, Zhejiang Province, China
| | - Li-Zhen Zhou
- Department of Gastroenterology, Lishui City People's Hospital, Lishui 323000, Zhejiang Province, China
| | - Qing-Qing Tang
- Zhiyuan Inspection Medical Institute, Hangzhou 310000, Zhejiang Province, China
| | - Fei Meng
- Zhiyuan Inspection Medical Institute, Hangzhou 310000, Zhejiang Province, China
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Camorlinga-Ponce M, Gómez-Delgado A, Aguilar-Zamora E, Torres RC, Giono-Cerezo S, Escobar-Ogaz A, Torres J. Phenotypic and Genotypic Antibiotic Resistance Patterns in Helicobacter pylori Strains From Ethnically Diverse Population in México. Front Cell Infect Microbiol 2021; 10:539115. [PMID: 33643927 PMCID: PMC7905308 DOI: 10.3389/fcimb.2020.539115] [Citation(s) in RCA: 17] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/28/2020] [Accepted: 12/30/2020] [Indexed: 12/11/2022] Open
Abstract
Helicobacter pylori strains carry a range of mutations in genes that confer antimicrobial resistance and restrict the available options to treat the infection. Latin America is a region that conserve a large number of indigenous communities relatively isolated that practice a traditional medicine without consumption of drugs. We hypothesized that rates of antibiotic resistance are lower in these communities. Recent progress in whole-genome sequencing has allowed the study of drug susceptibility by searching for the known mutations associated with antibiotic resistance. The aim of this work was to study trends of antibiotic resistance over a 20-year period in Mexican H. pylori strains and to compare susceptibility between strains from Mexican mestizos and from indigenous population; we also aimed to learn the prevalence of mutational patterns in genes gyrA, gyrB, rdxA, frxA, rpsU, omp11, dppA, and 23S rRNA and its association with phenotypic tests. Resistance to clarithromycin, metronidazole, amoxicillin and levofloxacin was determined in167 H. pylori isolates by E-test, and the occurrence of mutational patterns in specific genes was determined by whole genome sequencing (WGS). The trend of resistance over 20 years in mestizo isolates showed significant resistant increase for clarithromycin and levofloxacin to frequencies that banned its clinical use. Resistance in H. pylori isolates of native communities was lower for all antibiotics tested. Phenotypic resistance showed good to moderate correlation with genotypic tests. Genetic methods for characterizing antibiotic resistance require further validation in each population.
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Affiliation(s)
- Margarita Camorlinga-Ponce
- Unidad de Investigación en Enfermedades Infecciosas, UMAE Pediatría, Instituto Mexicano del Seguro Social, Ciudad de México, Mexico
| | - Alejandro Gómez-Delgado
- Unidad de Investigación en Enfermedades Infecciosas, UMAE Pediatría, Instituto Mexicano del Seguro Social, Ciudad de México, Mexico
| | - Emmanuel Aguilar-Zamora
- Unidad de Investigación en Enfermedades Infecciosas, UMAE Pediatría, Instituto Mexicano del Seguro Social, Ciudad de México, Mexico.,Posgrado en Biomedicina y Biotecnología Molecular, Escuela Nacional de Ciencias Biológicas, Instituto Politécnico Nacional, Ciudad de México, Mexico
| | - Roberto C Torres
- Unidad de Investigación en Enfermedades Infecciosas, UMAE Pediatría, Instituto Mexicano del Seguro Social, Ciudad de México, Mexico
| | - Silvia Giono-Cerezo
- Departamento de Microbiología, Escuela Nacional de Ciencias Biológicas, Instituto Politécnico Nacional, Ciudad de México, Mexico
| | - Antonio Escobar-Ogaz
- Unidad de Investigación en Enfermedades Infecciosas, UMAE Pediatría, Instituto Mexicano del Seguro Social, Ciudad de México, Mexico
| | - Javier Torres
- Unidad de Investigación en Enfermedades Infecciosas, UMAE Pediatría, Instituto Mexicano del Seguro Social, Ciudad de México, Mexico
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22
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Sholeh M, Maleki F, Krutova M, Bavari S, Golmoradi R, Sadeghifard N, Amiriani T, Kouhsari E. The increasing antimicrobial resistance of Helicobacter pylori in Iran: A systematic review and meta-analysis. Helicobacter 2020; 25:e12730. [PMID: 32705749 DOI: 10.1111/hel.12730] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/08/2020] [Revised: 06/12/2020] [Accepted: 06/28/2020] [Indexed: 12/23/2022]
Abstract
BACKGROUND Antimicrobial resistance of Helicobacter pylori can result in eradication failure. Metadata on the antimicrobial resistance of H pylori in Iran could help to formulate H pylori eradication strategies in Iran. METHODS A systematic review was performed after searching in MEDLINE, Scopus, Embase, Web of Science, and the Cochrane Library. A meta-analysis was performed, and a comparison of the rates between children and adults; time periods (1999-2010, 2011-2016, 2017-2019); and the methods used was carried out. RESULTS A total of 66 studies investigating 5936 H pylori isolates were analyzed. The weighted pooled resistance (WPR) rates were as follows: clarithromycin 21% (95% CI 16-26), metronidazole 62% (95% 57-67), clarithromycin in combination with metronidazole 16% (95% CI 10-23), ciprofloxacin 24% (95% CI 15-33), levofloxacin 18% (95% CI 9-30), erythromycin 29% (95% CI 12-50), furazolidone 13% (95% CI 4-27), tetracycline 8% (95% CI 5-13), and amoxicillin 15% (95% CI 9-22). During the three time periods, there was an increased resistance to amoxicillin, clarithromycin, ciprofloxacin, furazolidone, and tetracycline (P ˂ .05). Furazolidone and a clarithromycin/metronidazole combination had the higher resistance rates in children (P ˂ .05). CONCLUSION An increasing rate of resistance to amoxicillin, clarithromycin, ciprofloxacin, furazolidone, and tetracycline in Iranian H pylori isolates was identified. In children, the resistance to furazolidone and a combination of clarithromycin and metronidazole is higher compared to adults. As a stable, high resistance to metronidazole was found in children and adults in all Iranian provinces, we suggest that metronidazole should not be included in the Iranian H pylori eradication scheme.
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Affiliation(s)
- Mohammad Sholeh
- Department of Microbiology, Faculty of Medicine, Iran University of Medical Sciences, Tehran, Iran
| | - Farajolah Maleki
- Department of Laboratory Sciences, School of Allied Medical Sciences, Ilam University of Medical sciences, Ilam, Iran
| | - Marcela Krutova
- Department of Medical Microbiology, Charles University, 2nd Faculty of Medicine and Motol University Hospital, Prague, Czech Republic
| | - Shirin Bavari
- Department of Microbiology, Faculty of Medicine, Iran University of Medical Sciences, Tehran, Iran
| | - Rezvan Golmoradi
- Department of Microbiology, Faculty of Medicine, Iran University of Medical Sciences, Tehran, Iran
| | - Nourkhoda Sadeghifard
- Clinical Microbiology Research Center, Ilam University of Medical Sciences, Ilam, Iran
| | - Taghi Amiriani
- Golestan Research Center of Gastroenterology and Hepatology, Golestan University of Medical Sciences, Gorgan, Iran
| | - Ebrahim Kouhsari
- Clinical Microbiology Research Center, Ilam University of Medical Sciences, Ilam, Iran.,Laboratory Sciences Research Center, Golestan University of Medical Sciences, Gorgan, Iran
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23
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Wang YH, Wang FF, Gong XL, Yan LL, Zhao QY, Song YP, Zhao RL, He YJ, Zhou L, Liu DS, Xie Y. Genotype profiles of Helicobacter pylori from gastric biopsies and strains with antimicrobial-induced resistance. Therap Adv Gastroenterol 2020; 13:1756284820952596. [PMID: 33029198 PMCID: PMC7522827 DOI: 10.1177/1756284820952596] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/23/2020] [Accepted: 07/30/2020] [Indexed: 02/04/2023] Open
Abstract
BACKGROUND AND AIMS The genotypic method could significantly shorten the time needed to obtain antibiotic susceptibility data for Helicobacter pylori. The aim of this study was to explore the profile of H. pylori from gastric biopsies and strains with antibiotic-induced resistance. METHODS A total of 124 gastric biopsies were used to perform gene sequencing and to perform bacterial culture and susceptibility testing. Seven susceptible strains were selected to develop resistance to clarithromycin, levofloxacin, and metronidazole. Four susceptible strains were selected to transfer candidate mutations. The genotype profiles of these groups were analyzed by sequencing analysis. The antibiotic susceptibility of these strains was detected using the E-test method. RESULTS Phenotypic resistance to clarithromycin, levofloxacin, and metronidazole was observed in 35.5%, 40.0%, and 79.8% strains, respectively. Point mutations in 23 S rRNA, gyrA, and rdxA genes were observed in 39.5%, 38.7%, and 86.3% of gastric biopsies, respectively. The A2143G mutation in the 23S rRNA occurs in most clarithromycin-resistant samples. The A2142C point mutation showed a higher efficacy than A2142G and A2143G for inducing clarithromycin resistance. The D91N and N87K mutations in gyrA occurs in most levofloxacin-resistant samples, and double point mutations showed a higher efficacy than single mutations for inducing levofloxacin resistance. Phenotypic resistance and mutations in rdxA lacked consistency. CONCLUSION Genotype-based gastric biopsy analysis was reliable for determining clarithromycin and levofloxacin resistance. A2143G in 23S rRNA and N87K/D91N in the gyrA gene occurred in most resistant strains. Mutations in the rdxA gene were not good indicators of metronidazole resistance.
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Affiliation(s)
| | | | | | - Li-li Yan
- Department of Medical College, Nanchang University, Nanchang, Jiangxi Province, China
| | - Qiao-yun Zhao
- Department of Gastroenterology, The First Affiliated Hospital of Nanchang University, Nanchang, Jiangxi Province, China
| | - Yan-ping Song
- Department of Gastroenterology, The First Affiliated Hospital of Nanchang University, Nanchang, Jiangxi Province, China
| | - Ru-lin Zhao
- Department of Gastroenterology, The First Affiliated Hospital of Nanchang University, Nanchang, Jiangxi Province, China
| | - Ya-jing He
- Department of Gastroenterology, The First Affiliated Hospital of Nanchang University, Nanchang, Jiangxi Province, China
| | - Linfu Zhou
- Department of Biochemistry and Molecular Biology, Zhejiang University School of Medicine, Hangzhou, Zhejiang Province, China
| | - Dong-sheng Liu
- Department of Gastroenterology, The First Affiliated Hospital of Nanchang University, 17 Yongwai Zheng Street, Nanchang, Jiangxi Province, 330000, China
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24
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O'Connor A, Furuta T, Gisbert JP, O'Morain C. Review - Treatment of Helicobacter pylori infection 2020. Helicobacter 2020; 25 Suppl 1:e12743. [PMID: 32918350 DOI: 10.1111/hel.12743] [Citation(s) in RCA: 25] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/11/2022]
Abstract
This review summarizes important studies regarding Helicobacter pylori therapy published from April 2019 to April 2020. The main themes that emerge involve studies assessing antibiotic resistance, and there is also growing momentum behind the utility of vonoprazan as an alternative to proton pump inhibitor (PPI) therapy and also bismuth-based regimens as a first-line regimen. Antibiotic resistance is rising wherever it is being assessed, and clarithromycin resistance in particular has reached a point where it may no longer be a viable therapy without previous testing in many regions of the world. The evidence for the efficacy of a bismuth-based quadruple therapy as a first-line therapy is now very clearly established, and there is substantial evidence that it is the best performing first-line therapy. The utility of vonoprazan as an alternative to PPI therapy, especially in resistant and difficult-to-treat groups, has also been considered in great detail this year, and it may offer an opportunity in the near future to reduce the problem of antibiotic resistance.
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Affiliation(s)
- Anthony O'Connor
- Department of Gastroenterology, Tallaght University Hospital/Trinity College, Dublin, Ireland
| | - Takahisa Furuta
- The Center for Clinical Research, Hamamatsu University School of Medicine, Hamamatsu, Japan
| | - Javier P Gisbert
- Gastroenterology Unit, Hospital Universitario de La Princesa, Instituto de Investigación Sanitaria Princesa (IIS-IP), Universidad Autónoma de Madrid (UAM), Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBEREHD), Madrid, Spain
| | - Colm O'Morain
- Department of Gastroenterology, Tallaght University Hospital/Trinity College, Dublin, Ireland
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25
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Alihosseini S, Ghotaslou R, Heravi FS, Ahmadian Z, Leylabadlo HE. Management of antibiotic-resistant Helicobacter pylori infection: current perspective in Iran. J Chemother 2020; 32:273-285. [PMID: 32657237 DOI: 10.1080/1120009x.2020.1790889] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/23/2022]
Abstract
Helicobacter pylori is a common gastric bacterial pathogen implicated in the pathogenesis of many digestive tract disorders. H. pylori infection prevalence has been reported alarmingly in Iran. A plethora of studies have been conducted to evaluate the efficiency of first-line and second-line eradication attempts in patients diagnosed with H. pylori infections in Iran. The present study, was evaluated the efficacy of first-line and second-line therapy in H. pylori infections in Iran. We aimed to consider the literature review of the various library and electronic databases (Science Direct, PubMed, and Google Scholar) until 2020. The frequency of bacterial resistance to tetracycline, ampicillin, trimethoprim, erythromycin, ofloxacin, and metronidazolewas found to be high in Iran, while the most effective antibiotics were clarithromycin, rifampin, rifampicin, tetracycline, amoxicillin, ciprofloxacin, levofloxacin, moxifloxacin, and azithromycin. The therapeutic choice for H. pylori eradication in Iran could be quadruple therapy using two antibiotics amoxicillin and metronidazole/clarithromycin for the first-line regimen, and a combination of furazolidone plus tetracycline/amoxicillin and bismuth plus proton pump inhibitor for the second-line regimen. Due to increased antibiotic resistance in our region, empirical therapy must be replaced by more targeted treatment based on antimicrobial drug resistance profiles obtained from patients. Although we limited our investigation on the H. pylori eradication regimens in Iran, the results can be generalized to any region as long as the patterns of resistance are the same.
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Affiliation(s)
- Samin Alihosseini
- Immunology Research Center, Tabriz University of Medical Sciences, Tabriz, Iran.,Student Research Committee, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Reza Ghotaslou
- Immunology Research Center, Tabriz University of Medical Sciences, Tabriz, Iran.,Department of Bacteriology and Virology, Faculty of Medicine, Tabriz University of Medical Sciences, Tabriz, Iran
| | | | - Zainab Ahmadian
- Department of Pharmaceutics, School of Pharmacy, Zanjan University of Medical Science, Zanjan, Iran
| | - Hamed Ebrahimzadeh Leylabadlo
- Immunology Research Center, Tabriz University of Medical Sciences, Tabriz, Iran.,Student Research Committee, Tabriz University of Medical Sciences, Tabriz, Iran.,Department of Bacteriology and Virology, Faculty of Medicine, Tabriz University of Medical Sciences, Tabriz, Iran
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26
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Khademi F, Sahebkar A. An Updated Systematic Review and Meta-Analysis on the Helicobacter pylori Antibiotic Resistance in Iran (2010-2020). Microb Drug Resist 2020; 26:1186-1194. [PMID: 32354289 DOI: 10.1089/mdr.2020.0088] [Citation(s) in RCA: 14] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/14/2022] Open
Abstract
This updated systematic review and meta-analysis followed two objectives: (1) to determine Helicobacter pylori antibiotic resistance in Iran during 2010-2020 and (2) to assess the trend of resistance from 1997 to 2020. A systematic search in multiple databases, including ISI Web of Knowledge, PubMed, Scopus, Google Scholar, and the Scientific Information Database (SID), was performed using MeSH-extracted keywords. Meta-analysis was done on extracted data from a total of 27 included citations published between 2010 and January 20, 2020. The overall mean prevalence of H. pylori resistance was 64.9% for metronidazole, 25.3% for clarithromycin, 20.7% for amoxicillin, 16.1% for tetracycline, 21.9% for levofloxacin, 22.8% for rifampicin, 27.2% for furazolidone, 32.3% for ciprofloxacin, and 38.7% for erythromycin. In addition, the prevalence of multidrug-resistant strains of H. pylori was 26.5% in Iran. The pooled prevalence of point mutations A2143G, A2142G, and A2142C associated with clarithromycin resistance were 46.6%, 37.2%, and 5.5%, respectively; mutations in frxA and rdxA genes associated with metronidazole resistance were 46.4% and 19.7%, respectively; gyrA and gyrB genes mutations among fluoroquinolone-resistant strains were 55.3% and 48.2%, respectively; and resistance associated with integrons was 47%. According to the present findings, resistance of H. pylori to antibiotics used for eradication therapy has reached an alarming level in Iran. Furthermore, the trend of H. pylori resistance has increased between 1997 and 2020. Hence, continuous surveillance on resistance patterns, logical prescription and appropriate consumption of antibiotics, and selecting effective therapeutic regimens in accordance with local resistance patterns are required to prevent further spread of resistance and ensuing treatment failures.
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Affiliation(s)
- Farzad Khademi
- Department of Microbiology, School of Medicine, Ardabil University of Medical Sciences, Ardabil, Iran
| | - Amirhossein Sahebkar
- Halal Research Center of IRI, FDA, Tehran, Iran.,Neurogenic Inflammation Research Center, Mashhad University of Medical Sciences, Mashhad, Iran.,Biotechnology Research Center, Pharmaceutical Technology Institute, Mashhad University of Medical Sciences, Mashhad, Iran
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27
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Li RJ, Dai YY, Qin C, Li XH, Qin YC, Pan Y, Huang YY, Huang ZS, Huang YQ. Treatment strategies and preventive methods for drug-resistant Helicobacter pylori infection. World J Meta-Anal 2020; 8:98-108. [DOI: 10.13105/wjma.v8.i2.98] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/26/2019] [Revised: 03/17/2020] [Accepted: 03/19/2020] [Indexed: 02/06/2023] Open
Abstract
The infection and drug resistance rates of Helicobacter pylori (H. pylori) are high and must be prevented and treated by better strategies. Based on recent research advances in this field as well as the results from our team and those on traditional Chinese medicine, we review the causes of drug resistance, and prevention and treatment strategies for drug-resistant H. pylori infection, with an aim to make suggestions for the development of new drugs, such as establishment of new target identification and screening systems, modification of existing drug structures, use of new technologies, application of natural products, and using a commercial compound library. This article may provide reference for eradication of drug-resistant H. pylori.
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Affiliation(s)
- Ru-Jia Li
- Research Center for Prevention and Treatment of Drug Resistant Microbial Infections, Youjiang Medical University for Nationalities, Baise 533000, Guangxi Zhuang Autonomous Region, China
| | - Yuan-Yuan Dai
- Research Center for Prevention and Treatment of Drug Resistant Microbial Infections, Youjiang Medical University for Nationalities, Baise 533000, Guangxi Zhuang Autonomous Region, China
| | - Chun Qin
- Research Center for Prevention and Treatment of Drug Resistant Microbial Infections, Youjiang Medical University for Nationalities, Baise 533000, Guangxi Zhuang Autonomous Region, China
| | - Xiao-Hua Li
- Research Center for Prevention and Treatment of Drug Resistant Microbial Infections, Youjiang Medical University for Nationalities, Baise 533000, Guangxi Zhuang Autonomous Region, China
| | - Yan-Chun Qin
- Research Center for Prevention and Treatment of Drug Resistant Microbial Infections, Youjiang Medical University for Nationalities, Baise 533000, Guangxi Zhuang Autonomous Region, China
| | - Yong Pan
- Research Center for Prevention and Treatment of Drug Resistant Microbial Infections, Youjiang Medical University for Nationalities, Baise 533000, Guangxi Zhuang Autonomous Region, China
| | - Yong-Yi Huang
- Research Center for Prevention and Treatment of Drug Resistant Microbial Infections, Youjiang Medical University for Nationalities, Baise 533000, Guangxi Zhuang Autonomous Region, China
| | - Zan-Song Huang
- Research Center for Prevention and Treatment of Drug Resistant Microbial Infections, Youjiang Medical University for Nationalities, Baise 533000, Guangxi Zhuang Autonomous Region, China
| | - Yan-Qiang Huang
- Research Center for Prevention and Treatment of Drug Resistant Microbial Infections, Youjiang Medical University for Nationalities, Baise 533000, Guangxi Zhuang Autonomous Region, China
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28
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Molecular Assessment of Resistance to Clarithromycin in Helicobacter pylori Strains Isolated from Patients with Dyspepsia by Fluorescent In Situ Hybridization in the Center of Iran. BIOMED RESEARCH INTERNATIONAL 2020; 2020:2304173. [PMID: 32309428 PMCID: PMC7140143 DOI: 10.1155/2020/2304173] [Citation(s) in RCA: 12] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 12/06/2019] [Revised: 03/03/2020] [Accepted: 03/17/2020] [Indexed: 12/11/2022]
Abstract
Background and Aims Helicobacter pylori is a common infectious bacterium mostly found in gastroduodenal diseases. The increased prevalence of clarithromycin-resistant H. pylori strains is a major challenge in the successful treatment of infections caused by this organism. The present study is aimed at detecting the clarithromycin resistance pattern of H. pylori strains isolated from gastric biopsies and evaluating point mutations of the 23S rRNA gene. Patients and methods. In the present descriptive cross-sectional study, 165 patients with gastrointestinal disorders, who were referred to the Endoscopy Center of Dr. Shariati Hospital of Isfahan, Iran, were enrolled from April to July 2018. H. pylori infection was diagnosed by culture, and susceptibility of the isolates to clarithromycin was assessed by the E-test. Minimum inhibitory concentration (MIC) values were obtained based on EUCAST recommendations. Also, fluorescence in situ hybridization (FISH) was used to determine point mutations associated with clarithromycin resistance. Results By using culturing, H. pylori was isolated from 50.3% (83/165) gastric biopsy specimens. The overall frequency of resistance to clarithromycin was 25.3% (21/83) by the E-test. In the resistance genotypic analysis, 19 isolates had mutations. The prevalence of A2143G and A2144G mutations was 68.4% (13/19) and 31.5% (6/19), respectively. A2143C mutation was not tracked in any isolate. Two isolates with MIC > 0.5 μg/mL had no mutations that could be related to other mechanisms of resistance. Conclusion As presented in the study, the high prevalence of clarithromycin-resistant H. pylori due to point mutations of the 23S rRNA gene indicates the necessity of revising the standard treatment regimen based on antibiotic susceptibility pattern of each region.
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29
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Marques AT, Vítor JMB, Santos A, Oleastro M, Vale FF. Trends in Helicobacter pylori resistance to clarithromycin: from phenotypic to genomic approaches. Microb Genom 2020; 6:e000344. [PMID: 32118532 PMCID: PMC7200067 DOI: 10.1099/mgen.0.000344] [Citation(s) in RCA: 32] [Impact Index Per Article: 6.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/09/2019] [Accepted: 02/10/2020] [Indexed: 12/15/2022] Open
Abstract
For a long time Helicobacter pylori infections have been treated using the macrolide antibiotic, clarithromycin. Clarithromycin resistance is increasing worldwide and is the most common cause of H. pylori treatment failure. Here we review the mechanisms of antibiotic resistance to clarithromycin, detailing the individual and combinations of point mutations found in the 23S rRNA gene associated with resistance. Additionally, we consider the methods used to detect clarithromycin resistance, emphasizing the use of high-throughput next-generation sequencing methods, which were applied to 17 newly sequenced pairs of H. pylori strains isolated from the antrum and corpus of a recent colonized paediatric population. This set of isolates was composed of six pairs of resistant strains whose phenotype was associated with two point mutations found in the 23S rRNA gene: A2142C and A2143G. Other point mutations were found simultaneously in the same gene, but, according to our results, it is unlikely that they contribute to resistance. Further, among susceptible isolates, genomic variations compatible with mutations previously associated with clarithromycin resistance were detected. Exposure to clarithromycin may select low-frequency variants, resulting in a progressive increase in the resistance rate due to selection pressure.
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Affiliation(s)
- Andreia T. Marques
- Host–Pathogen Interactions Unit, Research Institute for Medicines (iMed-ULisboa), Faculty of Pharmacy, Universidade de Lisboa, Lisboa, Portugal
| | - Jorge M. B. Vítor
- Host–Pathogen Interactions Unit, Research Institute for Medicines (iMed-ULisboa), Faculty of Pharmacy, Universidade de Lisboa, Lisboa, Portugal
- Department of Biochemistry and Human Biology, Faculty of Pharmacy, Universidade de Lisboa, 1649 003 Lisbon, Portugal
| | - Andrea Santos
- National Reference Laboratory for Gastrointestinal Infections, Department of Infectious Diseases, National Institute of Health Dr Ricardo Jorge, Lisbon, Portugal
| | - Mónica Oleastro
- National Reference Laboratory for Gastrointestinal Infections, Department of Infectious Diseases, National Institute of Health Dr Ricardo Jorge, Lisbon, Portugal
| | - Filipa F. Vale
- Host–Pathogen Interactions Unit, Research Institute for Medicines (iMed-ULisboa), Faculty of Pharmacy, Universidade de Lisboa, Lisboa, Portugal
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30
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Mashak Z, Jafariaskari S, Alavi I, Sakhaei Shahreza M, Safarpoor Dehkordi F. Phenotypic and Genotypic Assessment of Antibiotic Resistance and Genotyping of vacA, cagA, iceA, oipA, cagE, and babA2 Alleles of Helicobacter pylori Bacteria Isolated from Raw Meat. Infect Drug Resist 2020; 13:257-272. [PMID: 32099418 PMCID: PMC6996226 DOI: 10.2147/idr.s233612] [Citation(s) in RCA: 12] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/06/2019] [Accepted: 12/17/2019] [Indexed: 12/18/2022] Open
Abstract
BACKGROUND Foodstuffs with animal origins, particularly meat, are likely reservoirs of Helicobacter pylori. PURPOSE An existing survey was accompanied to assess phenotypic and genotypic profiles of antibiotic resistance and genotyping of vacA, cagA, cagE, iceA, oipA, and babA2 alleles amongst the H. pylori bacteria recovered from raw meat. METHODS Six-hundred raw meat samples were collected and cultured. H. pylori isolates were tested using disk diffusion and PCR identification of antibiotic resistance genes and genotyping. RESULTS Fifty-two out of 600 (8.66%) raw meat samples were contaminated with H. pylori. Raw ovine meat (13.07%) had the uppermost contamination. H. pylori bacteria displayed the uppermost incidence of resistance toward tetracycline (82.69%), erythromycin (80.76%), trimethoprim (65.38%), levofloxacin (63.46%), and amoxicillin (63.46%). All H. pylori bacteria had at least resistance toward one antibiotic, even though incidence of resistance toward more than eight antibiotics was 28.84%. Total distribution of rdxA, pbp1A, gyrA, and cla antibiotic resistance genes were 59.61%, 51.92%, 69.23%, and 65.38%, respectively. VacA s1a (84.61%), s2 (76.92%), m1a (50%), m2 (39.13%), iceA1 (38.46%), and cagA (55.76%) were the most generally perceived alleles. S1am1a (63.46%), s2m1a (53.84%), s1am2 (51.92%), and s2m2 (42.30%) were the most generally perceived genotyping patterns. Frequency of cagA-, oipA-, and babA2- genotypes were 44.23%, 73.07%, and 80.76%, respectively. A total of 196 combined genotyping patterns were also perceived. CONCLUSION The role of raw meat, particularly ovine meat, in transmission of virulent and resistant H. pylori bacteria was determined. VacA and cagA genotypes had the higher incidence. CagE-, babA2-, and oipA- H. pylori bacteria had the higher distribution. Supplementary surveys are compulsory to originate momentous relations between distribution of genotypes, antibiotic resistance, and antibiotic resistance genes.
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Affiliation(s)
- Zohreh Mashak
- Department of Food Hygiene, Faculty of Veterinary Medicine, Karaj Branch, Islamic Azad University, Karaj, Iran
| | - Sedigheh Jafariaskari
- Department of Parasitology, Faculty of Veterinary Medicine, University of Tehran, Tehran, Iran
| | - Iman Alavi
- Department of Microbiology, Faculty of Basic Sciences, Islamic Azad University, Shahrekord, Iran
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31
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Lin J, Zhang X, Wen Y, Chen H, She F. A Newly Discovered Drug Resistance Gene rfaF In Helicobacter pylori. Infect Drug Resist 2019; 12:3507-3514. [PMID: 31814739 PMCID: PMC6858805 DOI: 10.2147/idr.s231152] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/16/2019] [Accepted: 10/30/2019] [Indexed: 12/13/2022] Open
Abstract
BACKGROUND The purpose of this study was to understand the function of rfaF gene in Helicobacter pylori antibiotic resistance. METHODS The gene homologous recombination method was used for knockout and complementation of H. pylori rfaF gene. Various constructed strains were analysed for drug sensitivity to amoxicillin (AMO), tetracycline (TET), clarithromycin (CLA), metronidazole (MET), levofloxacin (LEV), and chloramphenicol (CHL) by agar plate dilution method. Drug sensitivity was further confirmed using a growth inhibition curve. Ethidium bromide (EB) accumulation experiments were performed to assess cell membrane permeability. PCR and sequence analysis were used to detect the rfaF gene. RESULTS The minimum inhibitory concentrations (MIC) of TET, CHL, AMO, and CLA in 11,637 rfaF knockout strain (ΔrfaF strain) were 4, 4, 2, and 2 times higher than those in 11,637 wild type (WT) strain, respectively. A multidrug-resistant (MDR) ΔrfaF strain also displayed the same trend; however, the degrees of increase were relatively small. Growth inhibition experiments indicated that the growth of the 11,637 ΔrfaF strain was higher with antibiotics at the MIC of the 11,637 WT strain than that of 11,637 rfaF-complemented strain (ΔrfaF/rfaF strain), whereas the 11,637 WT strain did not exhibit any growth. The 11,637 ΔrfaF strain was significantly reduced compared with the cumulative EB fluorescence intensity of the 11,637 WT and of 11,637ΔrfaF/rfaF strain, and the same trend appeared in the MDR strain. Among the 10 clinical strains, 9 clinical strains were found to have mutations in the conserved sequence of rfaF amino acids. CONCLUSION We found a new drug resistance gene, rfaF, in H. pylori, which changes the permeability of cell membrane to confer cross-resistance to AMO, TET, CLA, and CHL and is involved in clinical strain drug resistance. It can be used as a drug target.
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Affiliation(s)
- Jiansheng Lin
- Key Laboratory of Ministry of Education for Gastrointestinal Cancer, School of Basic Medical Sciences, Fujian Medical University, Fuzhou350122, People’s Republic of China
- Fujian Key Laboratory of Tumor Microbiology, School of Basic Medical Sciences, Fujian Medical University, Fuzhou350122, People’s Republic of China
| | - Xiaoyan Zhang
- Key Laboratory of Ministry of Education for Gastrointestinal Cancer, School of Basic Medical Sciences, Fujian Medical University, Fuzhou350122, People’s Republic of China
- Fujian Key Laboratory of Tumor Microbiology, School of Basic Medical Sciences, Fujian Medical University, Fuzhou350122, People’s Republic of China
| | - Yancheng Wen
- Key Laboratory of Ministry of Education for Gastrointestinal Cancer, School of Basic Medical Sciences, Fujian Medical University, Fuzhou350122, People’s Republic of China
- Fujian Key Laboratory of Tumor Microbiology, School of Basic Medical Sciences, Fujian Medical University, Fuzhou350122, People’s Republic of China
| | - Hao Chen
- Key Laboratory of Ministry of Education for Gastrointestinal Cancer, School of Basic Medical Sciences, Fujian Medical University, Fuzhou350122, People’s Republic of China
- Fujian Key Laboratory of Tumor Microbiology, School of Basic Medical Sciences, Fujian Medical University, Fuzhou350122, People’s Republic of China
| | - Feifei She
- Key Laboratory of Ministry of Education for Gastrointestinal Cancer, School of Basic Medical Sciences, Fujian Medical University, Fuzhou350122, People’s Republic of China
- Fujian Key Laboratory of Tumor Microbiology, School of Basic Medical Sciences, Fujian Medical University, Fuzhou350122, People’s Republic of China
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