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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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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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3
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Fayed B, Jagal J, Cagliani R, Kedia RA, Elsherbeny A, Bayraktutan H, Khoder G, Haider M. Co-administration of amoxicillin-loaded chitosan nanoparticles and inulin: A novel strategy for mitigating antibiotic resistance and preserving microbiota balance in Helicobacter pylori treatment. Int J Biol Macromol 2023; 253:126706. [PMID: 37673144 DOI: 10.1016/j.ijbiomac.2023.126706] [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: 07/06/2023] [Revised: 08/25/2023] [Accepted: 09/03/2023] [Indexed: 09/08/2023]
Abstract
Helicobacter pylori (H. pylori) is a causative agent of various gastrointestinal diseases and eradication mainly relies on antibiotic treatment, with (AMX) being a key component. However, rising antibiotic resistance in H. pylori necessitates the use of antibiotics combination therapy, often disrupting gut microbiota equilibrium leading to further health complications. This study investigates a novel strategy utilizing AMX-loaded chitosan nanoparticles (AMX-CS NPs), co-administered with prebiotic inulin to counteract H. pylori infection while preserving microbiota health. Following microbroth dilution method, AMX displayed efficacy against H. pylori, with a MIC50 of 48.34 ± 3.3 ng/mL, albeit with a detrimental impact on Lactobacillus casei (L. casei). The co-administration of inulin (500 μg/mL) with AMX restored L. casei viability while retaining the lethal effect on H. pylori. Encapsulation of AMX in CS-NPs via ionic gelation method, resulted in particles of 157.8 ± 3.85 nm in size and an entrapment efficiency (EE) of 86.44 ± 2.19 %. Moreover, AMX-CS NPs showed a sustained drug release pattern over 72 h with no detectable toxicity on human dermal fibroblasts cell lines. Encapsulation of AMX into CS NPs also reduced its MIC50 against H. pylori, while its co-administration with inulin maintained L. casei viability. Interestingly, treatment with AMX-CS NPs also reduced the expression of the efflux pump gene hefA in H. pylori. This dual treatment strategy offers a promising approach for more selective antimicrobial treatment, minimizing disruption to healthy microbial communities while effectively addressing pathogenic threats.
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Affiliation(s)
- Bahgat Fayed
- Research Institute of Medical & Health Sciences, University of Sharjah, 27272 Sharjah, United Arab Emirates; Chemistry of Natural and Microbial Product Department, National Research Centre, Cairo 12622, Egypt
| | - Jayalakshmi Jagal
- Research Institute of Medical & Health Sciences, University of Sharjah, 27272 Sharjah, United Arab Emirates
| | - Roberta Cagliani
- Research Institute of Medical & Health Sciences, University of Sharjah, 27272 Sharjah, United Arab Emirates
| | - Reena A Kedia
- Research Institute of Medical & Health Sciences, University of Sharjah, 27272 Sharjah, United Arab Emirates
| | - Amr Elsherbeny
- Division of Molecular Therapeutics and Formulation, School of Pharmacy, University of Nottingham, Nottingham NG7 2RD, United Kingdom; Biodiscovery Institute, School of Medicine, University of Nottingham, Nottingham NG7 2UH, United Kingdom
| | - Hulya Bayraktutan
- Division of Molecular Therapeutics and Formulation, School of Pharmacy, University of Nottingham, Nottingham NG7 2RD, United Kingdom; Biodiscovery Institute, School of Medicine, University of Nottingham, Nottingham NG7 2UH, United Kingdom
| | - Ghalia Khoder
- Research Institute of Medical & Health Sciences, University of Sharjah, 27272 Sharjah, United Arab Emirates; Department of Pharmaceutics and Pharmaceutical Technology, College of Pharmacy, University of Sharjah, 27272 Sharjah, United Arab Emirates.
| | - Mohamed Haider
- Research Institute of Medical & Health Sciences, University of Sharjah, 27272 Sharjah, United Arab Emirates; Department of Pharmaceutics and Pharmaceutical Technology, College of Pharmacy, University of Sharjah, 27272 Sharjah, United Arab Emirates.
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Ng HY, Leung WK, Cheung KS. Antibiotic Resistance, Susceptibility Testing and Stewardship in Helicobacter pylori Infection. Int J Mol Sci 2023; 24:11708. [PMID: 37511471 PMCID: PMC10380565 DOI: 10.3390/ijms241411708] [Citation(s) in RCA: 7] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/21/2023] [Revised: 07/12/2023] [Accepted: 07/17/2023] [Indexed: 07/30/2023] Open
Abstract
Despite the declining trend of Helicobacter pylori (H. pylori) prevalence around the globe, ongoing efforts are still needed to optimize current and future regimens in view of the increasing antibiotic resistance. The resistance of H. pylori to different antibiotics is caused by different molecular mechanisms, and advancements in sequencing technology have come a far way in broadening our understanding and in facilitating the testing of antibiotic susceptibility to H. pylori. In this literature review, we give an overview of the molecular mechanisms behind resistance, as well as discuss and compare different antibiotic susceptibility tests based on the latest research. We also discuss the principles of antibiotic stewardship and compare the performance of empirical therapies based on up-to-date resistance patterns and susceptibility-guided therapies in providing effective H. pylori treatment. Studies and clinical guidelines should ensure that the treatment being tested or recommended can reliably achieve a pre-agreed acceptable level of eradication rate and take into account the variations in antibiotic resistance across populations. Local, regional and international organizations must work together to establish routine antibiotic susceptibility surveillance programs and enforce antibiotic stewardship in the treatment of H. pylori, so that it can be managed in a sustainable and efficient manner.
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Affiliation(s)
- Ho-Yu Ng
- School of Clinical Medicine, The University of Hong Kong, Hong Kong, China
| | - Wai K Leung
- Department of Medicine, School of Clinical Medicine, The University of Hong Kong, Queen Mary Hospital, 102 Pokfulam Road, Hong Kong, China
| | - Ka-Shing Cheung
- Department of Medicine, School of Clinical Medicine, The University of Hong Kong, Queen Mary Hospital, 102 Pokfulam Road, Hong Kong, China
- Department of Medicine, The University of Hong Kong-Shenzhen Hospital, Shenzhen 518053, China
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Interplay between Amoxicillin Resistance and Osmotic Stress in Helicobacter pylori. J Bacteriol 2022; 204:e0004522. [PMID: 35389254 DOI: 10.1128/jb.00045-22] [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: 11/20/2022] Open
Abstract
Rising antibiotic resistance rates are a growing concern for all pathogens, including Helicobacter pylori. We previously examined the association of specific mutations in PBP1 with amoxicillin resistance and fitness in H. pylori and found that V374L and N562Y mutations were associated with resistance, but also resulted in fitness defects. Furthermore, we found that hyperosmotic stress differentially altered the fitness of strains bearing these mutations; survival of the V374L strain was decreased by hyperosmotic stress, but the N562Y strain showed increased cell survival relative to that of wild-type G27. The finding that amoxicillin-resistant strains show environmentally dictated changes in fitness suggests a previously unexplored interaction between amoxicillin resistance and osmotic stress in H. pylori. Here, we further characterized the interaction between osmotic stress and amoxicillin resistance. Wild-type and isogenic PBP1 mutant strains were exposed to amoxicillin, various osmotic stressors, or combined antibiotic and osmotic stress, and viability was monitored. While subinhibitory concentrations of NaCl did not affect H. pylori viability, the combination of NaCl and amoxicillin resulted in synergistic killing; this was true even for the antibiotic-resistant strains. Moreover, similar synergy was found with other beta-lactams, but not with antibiotics that did not target the cell wall. Similar synergistic killing was also demonstrated when KCl was utilized as the osmotic stressor. Conversely, osmolar equivalent concentrations of sucrose antagonized amoxicillin-mediated killing. Taken together, our results support a previously unrecognized interaction between amoxicillin resistance and osmotic stress in H. pylori. These findings have interesting implications for the effectiveness of antibiotic therapy for this pathogen. IMPORTANCE Rising antibiotic resistance rates in H. pylori are associated with increased rates of treatment failure. Understanding how stressors impact antibiotic resistance may shed light on the development of future treatment strategies. Previous studies found that mutations in PBP1 that conferred resistance to amoxicillin were also associated with a decrease in bacterial fitness. The current study demonstrated that osmotic stress can enhance beta lactam-mediated killing of H. pylori. The source of osmotic stress was found to be important for these interactions. Given that relatively little is known about how H. pylori responds to osmotic stress, these findings fill important knowledge gaps on this topic and provide interesting implications for the effectiveness of antibiotic therapy for this pathogen.
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You Y, Thorell K, He L, Yahara K, Yamaoka Y, Cha JH, Murakami K, Katsura Y, Kobayashi I, Falush D, Zhang J. Genomic differentiation within East Asian Helicobacter pylori. Microb Genom 2022; 8. [PMID: 35188454 PMCID: PMC8942036 DOI: 10.1099/mgen.0.000676] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/23/2022] Open
Abstract
The East Asian region, including China, Japan and Korea, accounts for half of gastric cancer deaths. However, different areas have contrasting gastric cancer incidences and the population structure of Helicobacter pylori in this ethnically diverse region is yet unknown. We aimed to investigate genomic differences in H. pylori between these areas to identify sequence polymorphisms associated with increased cancer risk. We analysed 381 H. pylori genomes collected from different areas of the three countries using phylogenetic and population genetic tools to characterize population differentiation. The functional consequences of SNPs with a highest fixation index (Fst) between subpopulations were examined by mapping amino acid changes on 3D protein structure, solved or modelled. Overall, 329/381 genomes belonged to the previously identified hspEAsia population indicating that import of bacteria from other regions of the world has been uncommon. Seven subregional clusters were found within hspEAsia, related to subpopulations with various ethnicities, geographies and gastric cancer risks. Subpopulation-specific amino acid changes were found in multidrug exporters (hefC), transporters (frpB-4), outer membrane proteins (hopI) and several genes involved in host interaction, such as a catalase site, involved in H2O2 entrance, and a flagellin site mimicking host glycosylation. Several of the top hits, including frpB-4, hefC, alpB/hopB and hofC, have been found to be differentiated within the Americas in previous studies, indicating that a handful of genes may be key to local geographic adaptation. H. pylori within East Asia are not homogeneous but have become differentiated geographically at multiple loci that might have facilitated adaptation to local conditions and hosts. This has important implications for further evaluation of these changes in relation to the varying gastric cancer incidence between geographical areas in this region.
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Affiliation(s)
- Yuanhai You
- State Key Laboratory of Infectious Disease Prevention and Control, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, National Institute for Communicable Disease Control and Prevention, Chinese Center for Disease Control and Prevention, Beijing, PR China
| | - Kaisa Thorell
- Department of Clinical Microbiology, Sahlgrenska University Hospital, Västra Götaland 12 Region, Gothenburg, Sweden
- Department of Infectious Diseases, Sahlgrenska Academy, University of Gothenburg, Sweden
| | - Lihua He
- State Key Laboratory of Infectious Disease Prevention and Control, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, National Institute for Communicable Disease Control and Prevention, Chinese Center for Disease Control and Prevention, Beijing, PR China
| | - Koji Yahara
- Antimicrobial Resistance Research Center, National Institute of Infectious Diseases, Tokyo, Japan
| | - Yoshio Yamaoka
- Department of Environmental and Preventive Medicine, Oita University Faculty of Medicine, Oita, Japan
| | - Jeong-Heon Cha
- Department of Oral Biology, BK21 Plus Project, Yonsei University College of Dentistry, Seoul, Republic of Korea
| | - Kazunari Murakami
- Department of Gastroenterology, Faculty of Medicine, Oita University, Oita, Japan
| | - Yukako Katsura
- Primate Research Institute, Kyoto University, Inuyama, Japan
| | - Ichizo Kobayashi
- Department of Computational Biology and Medical Sciences (formerly Department of Medical Genome Sciences), Graduate School of Frontier Sciences, University of Tokyo, Tokyo, Japan
- Department of Infectious Diseases, Kyorin University School of Medicine, Mitaka-shi, Tokyo, Japan
- I2BC, University of Paris-Saclay, Gif-sur-Yvette, France
- Research Center for Micro-Nano Technology, Hosei University, Koganei-shi, Tokyo, Japan
- Institute of Medical Science, University of Tokyo, Minato-ku, Tokyo, Japan
| | - Daniel Falush
- The Center for Microbes, Development and Health, Key Laboratory of Molecular Virology and Immunology, Institut Pasteur of Shanghai, Chinese Academy of Sciences, Shanghai, PR China
| | - Jianzhong Zhang
- State Key Laboratory of Infectious Disease Prevention and Control, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, National Institute for Communicable Disease Control and Prevention, Chinese Center for Disease Control and Prevention, Beijing, PR China
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Genetic and Transcriptomic Variations for Amoxicillin Resistance in Helicobacter pylori under Cryopreservation. Pathogens 2021; 10:pathogens10060676. [PMID: 34070823 PMCID: PMC8229390 DOI: 10.3390/pathogens10060676] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/15/2021] [Revised: 05/02/2021] [Accepted: 05/27/2021] [Indexed: 11/17/2022] Open
Abstract
Some amoxicillin-resistant strains of H. pylori show a sharp decrease in amoxicillin resistance after freezing. In China, most clinical gastric mucosal specimens are frozen and transported for isolation and drug susceptibility testing for H. pylori, which may lead to an underestimation of the amoxicillin resistance. The objective of this study is to investigated reasons for the decreased amoxicillin resistance after cryopreservation. A high-level amoxicillin-resistant clone (NX24r) was obtained through amoxicillin pressure screening. After cryopreservation at -80 °C for 3 months, the minimum inhibitory concentration (MIC) of NX24r was reduced sharply. Mutations and changes of transcriptome were analyzed after amoxicillin screening and cryopreservation. Mutations in PBP1 (I370T, E428K, T556S) and HefC (M337K, L378F, D976V) were detected in NX24r, which may be the main reason for the induced amoxicillin resistance. No mutations were found in PBP1 or HefC after cryopreservation. However, transcriptome analysis showed that down-regulated genes in the cryopreserved clone were significantly enriched in plasma membrane (GO:0005886), including lepB, secD, gluP, hp0871 and hp1071. These plasma membrane genes are involved in the biosynthesis and transport function of the membrane. The decreased amoxicillin resistance after cryopreservation may be related to the down-regulation of genes involved in membrane structure and transport function.
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Cai Y, Wang C, Chen Z, Xu Z, Li H, Li W, Sun Y. Transporters HP0939, HP0497, and HP0471 participate in intrinsic multidrug resistance and biofilm formation in Helicobacter pylori by enhancing drug efflux. Helicobacter 2020; 25:e12715. [PMID: 32548895 DOI: 10.1111/hel.12715] [Citation(s) in RCA: 17] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/05/2020] [Revised: 05/17/2020] [Accepted: 05/26/2020] [Indexed: 02/06/2023]
Abstract
BACKGROUND The multidrug resistance of Helicobacter pylori is becoming an increasingly serious issue. It is therefore necessary to study the mechanism of multidrug resistance of H pylori. We have previously identified that the HP0939, HP0497, and HP0471 transporters affect the efflux of drugs from H pylori. As efflux pumps participate in bacterial multidrug resistance and biofilm formation, we hypothesized that these transporters could be involved in the multidrug resistance and biofilm formation of H pylori. MATERIALS AND METHODS We therefore constructed three knockout strains, Δhp0939, Δhp0497, and Δhp0471, and three high-expression strains, Hp0939he , Hp0497he , and Hp0471he , using the wild-type (WT) 26 695 strain of H pylori as the template. The minimum inhibitory concentration (MIC) and minimum bactericidal concentration (MBC) of wild strains, knockout strains, and high-expression strains to amoxicillin, metronidazole, and other antibiotics were measured. The efflux capacity of high-expression strains and wild strains was compared by Hoechst 33 342 accumulation assay. RESULTS Determination of the MIC and MBC of the antibiotics revealed that the knockout strains were more sensitive to antibiotics, while the high-expression strains were less sensitive to antibiotics, compared to the WT. The ability of the high-expression strains to efflux drugs was significantly higher than that of the WT. We also induced H pylori to form biofilms, and observed that the knockout strains could barely form biofilms and were more sensitive to several antibiotics, compared to the WT. The mRNA expression of hp0939, hp0497, and hp0471 in the clinically sensitive and multidrug-resistant strains was determined, and it was found that these genes were highly expressed in the multidrug-resistant strains that were isolated from the clinics. CONCLUSIONS In this study, we found three transporters involved in intrinsic multidrug resistance of H pylori.
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Affiliation(s)
- Yuying Cai
- Department of Microbiology, Key Laboratory of Medical Microbiology and Parasitology, Guizhou Medical University, Guiyang, China.,Institute of Pathogen Biology, School of Basic Medical Sciences, Shandong University, Jinan, China
| | - Caixia Wang
- Department of Microbiology, Key Laboratory of Medical Microbiology and Parasitology, Guizhou Medical University, Guiyang, China.,Institute of Pathogen Biology, School of Basic Medical Sciences, Shandong University, Jinan, China
| | - Zhenghong Chen
- Department of Microbiology, Key Laboratory of Medical Microbiology and Parasitology, Guizhou Medical University, Guiyang, China
| | - Zhengzheng Xu
- Department of Microbiology, Key Laboratory for Experimental Teratology of Ministry of Education, Key Laboratory of Infection and Immunology of Shandong Province, School of Basic Medicine, Shandong University, Jinan, China
| | - Huanjie Li
- Department of Microbiology, Key Laboratory for Experimental Teratology of Ministry of Education, Key Laboratory of Infection and Immunology of Shandong Province, School of Basic Medicine, Shandong University, Jinan, China
| | - Wenjuan Li
- Department of Microbiology, Key Laboratory for Experimental Teratology of Ministry of Education, Key Laboratory of Infection and Immunology of Shandong Province, School of Basic Medicine, Shandong University, Jinan, China
| | - Yundong Sun
- Department of Microbiology, Key Laboratory for Experimental Teratology of Ministry of Education, Key Laboratory of Infection and Immunology of Shandong Province, School of Basic Medicine, Shandong University, Jinan, China
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In Vitro Activity of Sertraline, an Antidepressant, Against Antibiotic-Susceptible and Antibiotic-Resistant Helicobacter pylori Strains. Pathogens 2019; 8:pathogens8040228. [PMID: 31717683 PMCID: PMC6963513 DOI: 10.3390/pathogens8040228] [Citation(s) in RCA: 14] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/25/2019] [Revised: 11/02/2019] [Accepted: 11/08/2019] [Indexed: 12/19/2022] Open
Abstract
Antibiotic resistance of Helicobacter pylori, a spiral bacterium associated with gastric diseases, is a topic that has been intensively discussed in last decades. Recent discoveries indicate promising antimicrobial and antibiotic-potentiating properties of sertraline (SER), an antidepressant substance. The aim of the study, therefore, was to determine the antibacterial activity of SER in relation to antibiotic-sensitive and antibiotic-resistant H. pylori strains. The antimicrobial tests were performed using a diffusion-disk method, microdilution method, and time-killing assay. The interaction between SER and antibiotics (amoxicillin, clarithromycin, tetracycline, and metronidazole) was determined by using a checkerboard method. In addition, the study was expanded to include observations by light, fluorescence, and scanning electron microscopy. The growth inhibition zones were in the range of 19–37 mm for discs impregnated with 2 mg of SER. The minimal inhibitory concentrations (MICs) and minimal bactericidal concentrations (MBCs) counted for 2–8 µg/mL and 4–8 µg/mL, respectively. The time-killing assay showed the time-dependent and concentration-dependent bactericidal activity of SER. Bacteria exposed to MBCs (but not sub-MICs and MICs ≠ MBCs) underwent morphological transformation into coccoid forms. This mechanism, however, was not protective because these cells after a 24-h incubation had a several-fold reduced green/red fluorescence ratio compared to the control. Using the checkerboard assay, a synergistic/additive interaction of SER with all four antibiotics tested was demonstrated. These results indicate that SER may be a promising anti-H. pylori compound.
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Helicobacter pylori: Multiple resistance in patients from Bogotá, Colombia. BIOMEDICA 2019; 39:125-134. [PMID: 31529855 DOI: 10.7705/biomedica.v39i3.4437] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Received: 04/01/2018] [Indexed: 12/14/2022]
Abstract
Introduction: The main cause for Helicobacter pylori infection treatment failure is antibiotic resistance, where clarithromycin and metronidazole play the main role. In Colombia, primary resistance as a consequence of the use of these two antibiotics and excessive levofloxacin use is above the accepted limit (13.6%, 83%, and 16%, respectively). Despite this fact, empirical therapies that include the combination of these antibiotics are used in patients with previous therapeutic failure.
Objective: To determine antibiotic resistance in patients previously treated for H. pylori in Bogotá, Colombia.
Materials and methods: We conducted a descriptive study that included ten isolates obtained from five patients with three or four previous failed treatments for H. pylori.
Antibiotic resistance to amoxicillin, clarithromycin, levofloxacin, and metronidazole was investigated by agar dilution and confirmed by DNA sequencing (Magrogen, Korea).
Results: Eight isolates were resistant to two or more antibiotics. All isolates were resistant to levofloxacin. Susceptibility patterns in isolates from the gastric antrum and the body of the stomach were different in three patients.
Conclusion: As far as we know, this is the first evidence of multiple H. pylori resistance in Colombia in previously treated patients. Results demonstrated the consequences of using an ineffective antibiotic scheme and the need to assess antibiotic susceptibility in different anatomical sites of the stomach. The consequences of multiple resistance decrease possible antibiotic effectiveness to eradicate H. pylori in the future.
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Hashemi SJ, Sheikh AF, Goodarzi H, Yadyad MJ, Seyedian SS, Aslani S, Assarzadegan MA. Genetic basis for metronidazole and clarithromycin resistance in Helicobacter pylori strains isolated from patients with gastroduodenal disorders. Infect Drug Resist 2019; 12:535-543. [PMID: 30881059 PMCID: PMC6404679 DOI: 10.2147/idr.s192942] [Citation(s) in RCA: 20] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/14/2022] Open
Abstract
BACKGROUND The aim of this study was to evaluate the antimicrobial resistance and genetic basis for metronidazole (Mtz) and clarithromycin (Cla) resistance in strains of Helicobacter pylori, isolated from patients with gastroduodenal disorders. PATIENTS AND METHODS A total of 157 H. pylori isolates (from 22 gastric cancer, 38 peptic ulcer disease, and 97 non-ulcer dyspepsia patients) were analyzed for drug susceptibility to Mtz and Cla, by gradient diffusion test (E-test, MAST). The PCR and sequence analysis of the rdxA and frxA for Mtz-resistant strains and the 23S rRNA for Cla-resistant strains were used to determine the genetic basis of drug resistance in H. pylori strains. Increased expression of TolC homologous genes (hefA) that upregulates efflux pump activity was determined in multidrug-resistant (MDR) strain of H. pylori by real-time PCR technique. RESULTS Among 157 H. pylori isolates, 32 (20.4%) strains were resistant to at least one of the antimicrobial agents. The highest resistance rate was attributed to Mtz (n=69, 43.94%). Among the resistant strains of H. pylori, 15 cases (9.55%) were detected as MDR. Mutations in the rdxA (85.5%) and A2143G point mutations (63.1%) in the 23S rRNA were the most common cause of resistance to Mtz and Cla in strains of H. pylori, respectively. In MDR strains, the rdxA mutation and A2143G-point mutation in the 23S rRNA were the most abundant mutations responsible for drug resistance. The relative expression of hefA in MDR strains (mean 3.706) was higher than the susceptible strains (mean 1.07). CONCLUSION Mutational inactivation and efflux pump overexpression are two mechanisms that increase the resistance to H. pylori antimicrobial agents and the rate of MDR strains. In Iran, the mutations of rdxA and frxA in Mtz-resistant strains and A2143G and A2142G of the 23S rRNA in Cla-resistant strains were significant. The screening for these mutations could help to prevent antibiotic resistance, and to determine the most effective anti-H. pylori drugs.
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Affiliation(s)
- Seyed Jalal Hashemi
- Infectious and Tropical Diseases Research Center, Health Research Institute, Ahvaz Jundishapur University of Medical Sciences, Ahvaz, Iran,
- Research Institute for Infectious Diseases of the Digestive System, School of Medicine, Ahvaz Jundishapur University of Medical Sciences, Ahvaz, Iran
- Division of Gastroenterology and Hepatology, Ahvaz Jundishapur University of Medical Sciences, Ahwaz, Iran
| | - Ahmad Farajzadeh Sheikh
- Infectious and Tropical Diseases Research Center, Health Research Institute, Ahvaz Jundishapur University of Medical Sciences, Ahvaz, Iran,
- Department of Microbiology, School of Medicine, Ahvaz Jundishapur University of Medical Sciences, Ahvaz, Iran,
| | - Hamed Goodarzi
- Infectious and Tropical Diseases Research Center, Health Research Institute, Ahvaz Jundishapur University of Medical Sciences, Ahvaz, Iran,
- Department of Microbiology, School of Medicine, Ahvaz Jundishapur University of Medical Sciences, Ahvaz, Iran,
- Molecular Biology Research Center, Baqiyatallah University of Medical Science, Tehran, Iran,
| | - Mohammad Jaafar Yadyad
- Infectious and Tropical Diseases Research Center, Health Research Institute, Ahvaz Jundishapur University of Medical Sciences, Ahvaz, Iran,
| | - Seyed Saeid Seyedian
- Alimentary Tract Research Center, Ahvaz Jundishapur University of Medical Sciences, Ahvaz, Iran
| | - Sajad Aslani
- Student Research Committee, Kerman University of Medical Sciences, Kerman, Iran
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Miftahussurur M, Aftab H, Shrestha PK, Sharma RP, Subsomwong P, Waskito LA, Doohan D, Fauzia KA, Yamaoka Y. Effective therapeutic regimens in two South Asian countries with high resistance to major Helicobacter pylori antibiotics. Antimicrob Resist Infect Control 2019; 8:40. [PMID: 30815255 PMCID: PMC6377755 DOI: 10.1186/s13756-019-0482-x] [Citation(s) in RCA: 19] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/27/2018] [Accepted: 01/30/2019] [Indexed: 12/17/2022] Open
Abstract
Background Nepal and Bangladesh have a high prevalence of Helicobacter pylori with high resistance rates to clarithromycin, metronidazole, and levofloxacin. Here, we evaluated the susceptibility and genetic mutations of 5 alternative antibiotics against isolates from both countries to obtain an effective treatment regimen for H. pylori eradication. Methods We used the agar dilution method to determine the minimal inhibitory concentration of 5 alternative antibiotics against 42 strains from Nepal and 56 from Bangladesh and performed whole genome mutation analysis. Results No resistance to furazolidone or rifabutin and a high susceptibility of sitafloxacin (95.2% in Nepal and 98.2% in Bangladesh) were observed. In contrast, resistance to rifaximin (52.4% in Nepal and 64.3% in Bangladesh) was high. Moreover, resistance to garenoxacin was higher in Bangladesh (51.6%) than in Nepal (28.6%, P = 0.041), most likely due to its correlation with levofloxacin resistance (P = 0.03). Garenoxacin and rifaximin were significantly correlated in Bangladesh (P = 0.014) and occurred together with all sitafloxacin-resistant strains. Mutations of gyrA could play a significant role in garenoxacin resistance, and double mutations of A87 and D91 were associated with sitafloxacin resistance. Analysis of the rpoB gene demonstrated well-known mutations, such as V657I, and several novel mutations, including I2619V, V2592 L, T2537A, and F2538 L. Conclusions Rifabutin can be cautiously implemented as therapy for H. pylori infection due to its interaction with the tuberculosis endemic in Bangladesh. The high susceptibility of furazolidone and sitafloxacin suggests their possible future application in Nepal and Bangladesh.
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Affiliation(s)
- Muhammad Miftahussurur
- Division of Gastroentero-Hepatology, Department of Internal Medicine, Faculty of Medicine-Dr. Soetomo Teaching Hospital, Universitas Airlangga, Surabaya, 60131 Indonesia
- Institute of Tropical Disease, Universitas Airlangga, Surabaya, 60115 Indonesia
| | - Hafeza Aftab
- Department of Gastroenterology, Dhaka Medical College and Hospital, Dhaka, Bangladesh
| | - Pradeep Krishna Shrestha
- Department of Gastroenterology, Maharajgunj Medical Campus, Tribhuvan University Teaching Hospital, Kathmandu, 44600 Nepal
| | - Rabi Prakash Sharma
- Department of Gastroenterology, Maharajgunj Medical Campus, Tribhuvan University Teaching Hospital, Kathmandu, 44600 Nepal
| | - Phawinee Subsomwong
- Department of Environmental and Preventive Medicine, Oita University Faculty of Medicine, 1-1 Idaigaoka, Hasama-machi, Yufu-City, Oita 879-5593 Japan
| | - Langgeng Agung Waskito
- Institute of Tropical Disease, Universitas Airlangga, Surabaya, 60115 Indonesia
- Department of Environmental and Preventive Medicine, Oita University Faculty of Medicine, 1-1 Idaigaoka, Hasama-machi, Yufu-City, Oita 879-5593 Japan
| | - Dalla Doohan
- Institute of Tropical Disease, Universitas Airlangga, Surabaya, 60115 Indonesia
- Department of Environmental and Preventive Medicine, Oita University Faculty of Medicine, 1-1 Idaigaoka, Hasama-machi, Yufu-City, Oita 879-5593 Japan
| | - Kartika Afrida Fauzia
- Institute of Tropical Disease, Universitas Airlangga, Surabaya, 60115 Indonesia
- Department of Environmental and Preventive Medicine, Oita University Faculty of Medicine, 1-1 Idaigaoka, Hasama-machi, Yufu-City, Oita 879-5593 Japan
| | - Yoshio Yamaoka
- Division of Gastroentero-Hepatology, Department of Internal Medicine, Faculty of Medicine-Dr. Soetomo Teaching Hospital, Universitas Airlangga, Surabaya, 60131 Indonesia
- Department of Environmental and Preventive Medicine, Oita University Faculty of Medicine, 1-1 Idaigaoka, Hasama-machi, Yufu-City, Oita 879-5593 Japan
- Global Oita Medical Advanced Research Center for Health, Oita University, Oita, 870-1192 Japan
- Department of Medicine, Gastroenterology and Hepatology Section, Baylor College of Medicine, Houston, TX 77030 USA
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Zanotti G, Cendron L. Structural Aspects of Helicobacter pylori Antibiotic Resistance. ADVANCES IN EXPERIMENTAL MEDICINE AND BIOLOGY 2019; 1149:227-241. [PMID: 31016632 DOI: 10.1007/5584_2019_368] [Citation(s) in RCA: 12] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 02/07/2023]
Abstract
Resistance to antibiotics of Helicobacter pylori infections is growing rapidly together with the need for more potent antimicrobials or novel strategies to recover the efficacy of the existing ones. Despite the main mechanisms according to which H. pylori acquires resistance are common to other microbial infections affecting humans, H. pylori has its own peculiarities, mostly due to the unique conditions experienced by the bacterium in the gastric niche. Possibly the most used of the antibiotics for H. pylori are those molecules that bind to the ribosome or to the DNA and RNA machinery, and in doing so they interfere with protein synthesis. Another important class is represented by molecules that binds to some enzyme essential for the bacterium survival, as in the case of enzymes involved in the bacterial wall biosynthesis. The mechanism used by the bacterium to fight antibiotics can be grouped in three classes: (i) mutations of some key residues in the protein that binds the inhibitor, (ii) regulation of the efflux systems or of the membrane permeability in order to reduce the uptake of the antibiotic, and (iii) other more complex indirect effects. Interestingly, the production of enzymes that degrade the antibiotics (as in the case of β-lactamases in many other bacteria) has not been clearly detected in H. pylori. The structural aspects of resistance players have not been object of extensive studies yet and the structure of very few H. pylori proteins involved in the resistance mechanisms are determined till now. Models of the proteins that play key roles in reducing antimicrobials susceptibility and their implications will be discussed in this chapter.
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Affiliation(s)
- Giuseppe Zanotti
- Department of Biomedical Sciences, University of Padua, Padua, Italy.
| | - Laura Cendron
- Department of Biology, University of Padua, Padua, Italy
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Abadi ATB. Resistance to clarithromycin and gastroenterologist's persistence roles in nomination for Helicobacter pylori as high priority pathogen by World Health Organization. World J Gastroenterol 2017; 23:6379-6384. [PMID: 29085187 PMCID: PMC5643263 DOI: 10.3748/wjg.v23.i35.6379] [Citation(s) in RCA: 29] [Impact Index Per Article: 3.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/03/2017] [Revised: 08/06/2017] [Accepted: 08/25/2017] [Indexed: 02/07/2023] Open
Abstract
Due to the increasing prevalence of clarithromycin resistance, future of management of Helicobacter pylori (H. pylori) infections need to be recognized. To now, clarithromycin was the best effective, well-tolerated and safe antibiotic used in treatment of the bacterium, but, increasing trend of resistance reduced efficacy of recommended regimens. Indeed, gastroenterologists are mostly unable to start appropriate therapy-according to the sensitivity profile-due to the certain difficulties in routine H. pylori culture procedure and being time consuming method. This announcement by World Health Organization (WHO) was an onset to reconsider current challenging dilemma about H. pylori clarithromycin resistant isolates. Therefore, investigating of various factors affecting this nomination by WHO is highly welcomed. In fact, WHO enumerated more than 16 pathogens which seriously threats human life and public health, thus better management or effective guidelines are necessary. Here for the first time, we nominated this phenomenon as ''gastroenterologist's persistence'' which should be equally investigated as antibiotic resistance. The ability of gastroenterologists to win the game against H. pylori infections is highly influenced by their collaboration with diagnostic laboratories to apply susceptibility patterns before any prescription. In conclusion, closer collaboration between two important partners (gastroenterologists and microbiologists) in management of H. pylori infection may hopefully trigger an era to remedy current crisis in clarithromycin resistance, a later gastric cancer can be practically preventable.
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Affiliation(s)
- Amin Talebi Bezmin Abadi
- Department of Bacteriology, Faculty of Medical Sciences, Tarbiat Modares University, Tehran 14115, Iran
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15
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Boyanova L, Gergova G, Markovska R, Kandilarov N, Davidkov L, Spassova Z, Mitov I. Primary Helicobacter pylori resistance in elderly patients over 20 years: A Bulgarian study. Diagn Microbiol Infect Dis 2017; 88:264-267. [PMID: 28506722 DOI: 10.1016/j.diagmicrobio.2017.05.001] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/15/2017] [Revised: 04/26/2017] [Accepted: 05/03/2017] [Indexed: 12/11/2022]
Abstract
We evaluated the antibiotic susceptibility of 233 Helicobacter pylori strains isolated in the period 2011-2016, involving 62 strains from elderly patients aged 66-93years and 171 strains from younger adults. To assess resistance evolution, primary resistance rates in 92 strains from as many patients aged ≥60years in 1996-2003 were compared with those in 85 strains from infected patients in the same age group in 2011-2016. In the patients aged >65years evaluated during the last 6 years, amoxicillin resistance according to EUCAST and prior breakpoints was 1.6 and 0%, respectively. Resistance rates were the same by both breakpoint systems to metronidazole (35.5%), clarithromycin (22.6%), tetracycline (1.6%) and levofloxacin (32.3%). In 2011-2016, there were no significant differences between resistance rates in the subjects aged >65years and the younger adults. Notably, during the last 6 years, double/triple resistance was found in 21.0% of the subjects aged >65years. Moreover, the prevalence of quinolone primary resistance (30.0%) was significantly (3.4-fold) higher than that (8.9%) observed in 1996-2003. Briefly, the presence of both combined resistance and a strikingly high primary levofloxacin resistance in the elderly implies a cautious antibiotic choice for H. pylori eradication. In vitro susceptibility testing of the strains is highly important in this age group. The results can be linked to more frequent comorbidities and co-infection treatment in older compared with younger patients and, additionally, to the national antibiotic consumption. The high prevalence of quinolone resistance in the elderly patients is an alarming finding.
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Affiliation(s)
- Lyudmila Boyanova
- Department of Medical Microbiology, Medical University of Sofia, Zdrave street 2, 1431 Sofia, Bulgaria.
| | - Galina Gergova
- Department of Medical Microbiology, Medical University of Sofia, Zdrave street 2, 1431 Sofia, Bulgaria
| | - Rumyana Markovska
- Department of Medical Microbiology, Medical University of Sofia, Zdrave street 2, 1431 Sofia, Bulgaria
| | - Nayden Kandilarov
- Department of General and Hepatobiliary Pancreatic Surgery, Medical University of Sofia, Sofia, Bulgaria
| | - Lyubomir Davidkov
- Department of Gastroenterology, University Hospital St. Ekaterina, Medical University of Sofia, Sofia, Bulgaria
| | - Zoya Spassova
- Department of Gastroenterology, University Hospital St. Ivan Rilski, Medical University of Sofia, Sofia, Bulgaria
| | - Ivan Mitov
- Department of Medical Microbiology, Medical University of Sofia, Zdrave street 2, 1431 Sofia, Bulgaria
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The Bifunctional Enzyme SpoT Is Involved in the Clarithromycin Tolerance of Helicobacter pylori by Upregulating the Transporters HP0939, HP1017, HP0497, and HP0471. Antimicrob Agents Chemother 2017; 61:AAC.02011-16. [PMID: 28242673 PMCID: PMC5404559 DOI: 10.1128/aac.02011-16] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/16/2016] [Accepted: 02/21/2017] [Indexed: 01/30/2023] Open
Abstract
Clarithromycin (CLA) is a commonly recommended drug for Helicobacter pylori eradication. However, the prevalence of CLA-resistant H. pylori is increasing. Although point mutations in the 23S rRNA are key factors for CLA resistance, other factors, including efflux pumps and regulation genes, are also involved in the resistance of H. pylori to CLA. Guanosine 3′-diphosphate 5′-triphosphate and guanosine 3′,5′-bispyrophosphate [(p)ppGpp)], which are synthesized by the bifunctional enzyme SpoT in H. pylori, play an important role for some bacteria to adapt to antibiotic pressure. Nevertheless, no related research involving H. pylori has been reported. In addition, transporters have been found to be related to bacterial drug resistance. Therefore, this study investigated the function of SpoT in H. pylori resistance to CLA by examining the shifts in the expression of transporters and explored the role of transporters in the CLA resistance of H. pylori. A ΔspoT strain was constructed in this study, and it was shown that SpoT is involved in H. pylori tolerance of CLA by upregulating the transporters HP0939, HP1017, HP0497, and HP0471. This was assessed using a series of molecular and biochemical experiments and a cDNA microarray. Additionally, the knockout of genes hp0939, hp0471, and hp0497 in the resistant strains caused a reduction or loss (the latter in the Δhp0497 strain) of resistance to CLA. Furthermore, the average expression levels of these four transporters in clinical CLA-resistant strains were considerably higher than those in clinical CLA-sensitive strains. Taken together, our results revealed a novel molecular mechanism of H. pylori adaption to CLA stress.
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17
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Attaran B, Falsafi T, Ghorbanmehr N. Effect of biofilm formation by clinical isolates of Helicobacter pylori on the efflux-mediated resistance to commonly used antibiotics. World J Gastroenterol 2017; 23:1163-1170. [PMID: 28275296 PMCID: PMC5323441 DOI: 10.3748/wjg.v23.i7.1163] [Citation(s) in RCA: 31] [Impact Index Per Article: 3.9] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/23/2016] [Revised: 11/11/2016] [Accepted: 01/04/2017] [Indexed: 02/06/2023] Open
Abstract
AIM To evaluate the role of biofilm formation on the resistance of Helicobacter pylori (H. pylori) to commonly prescribed antibiotics, the expression rates of resistance genes in biofilm-forming and planktonic cells were compared. METHODS A collection of 33 H. pylori isolates from children and adult patients with chronic infection were taken for the present study. The isolates were screened for biofilm formation ability, as well as for polymerase chain reaction (PCR) reaction with HP1165 and hp1165 efflux pump genes. Susceptibilities of the selected strains to antibiotic and differences between susceptibilities of planktonic and biofilm-forming cell populations were determined. Quantitative real-time PCR (qPCR) analysis was performed using 16S rRNA gene as a H. pylori-specific primer, and two efflux pumps-specific primers, hp1165 and hefA. RESULTS The strains were resistant to amoxicillin, metronidazole, and erythromycin, except for one strain, but they were all susceptible to tetracycline. Minimum bactericidal concentrations of antibiotics in the biofilm-forming cells were significantly higher than those of planktonic cells. qPCR demonstrated that the expression of efflux pump genes was significantly higher in the biofilm-forming cells as compared to the planktonic ones. CONCLUSION The present work demonstrated an association between H. pylori biofilm formation and decreased susceptibility to all the antibiotics tested. This decreased susceptibility to antibiotics was associated with enhanced functional activity of two efflux pumps: hp1165 and hefA.
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Hu Y, Zhang M, Lu B, Dai J. Helicobacter pylori and Antibiotic Resistance, A Continuing and Intractable Problem. Helicobacter 2016; 21:349-63. [PMID: 26822340 DOI: 10.1111/hel.12299] [Citation(s) in RCA: 100] [Impact Index Per Article: 11.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/06/2023]
Abstract
Helicobacter pylori, a human pathogen with a high global prevalence, is the causative pathogen for multiple gastrointestinal diseases, especially chronic gastritis, peptic ulcers, gastric mucosa-associated lymphoid tissue lymphoma, and gastric malignancies. Antibiotic therapies remain the mainstay for H. pylori eradication; however, this strategy is hampered by the emergence and spread of H. pylori antibiotic resistance. Exploring the mechanistic basis of this resistance is becoming one of the major research questions in contemporary biomedical research, as such knowledge could be exploited to devise novel rational avenues for counteracting the existing resistance and devising strategies to avoid the development of a novel anti-H. pylori medication. Encouragingly, important progress in this field has been made recently. Here, we attempt to review the current state and progress with respect to the molecular mechanism of antibiotic resistance for H. pylori. A picture is emerging in which mutations of various genes in H. pylori, resulting in decreased membrane permeability, altered oxidation-reduction potential, and a more efficient efflux pump system. The increased knowledge on these mechanisms produces hope that antibiotic resistance in H. pylori can ultimately be countered.
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Affiliation(s)
- Yue Hu
- Department of Gastroenterology, First Affiliated Hospital of Zhejiang Chinese Medical University, Hangzhou, China
| | - Meng Zhang
- Department of Gastroenterology, First Affiliated Hospital of Zhejiang Chinese Medical University, Hangzhou, China
| | - Bin Lu
- Department of Gastroenterology, First Affiliated Hospital of Zhejiang Chinese Medical University, Hangzhou, China.
| | - Jinfeng Dai
- Department of Gastroenterology, First Affiliated Hospital of Zhejiang Chinese Medical University, Hangzhou, China
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19
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Falsafi T, Ehsani A, Attaran B, Niknam V. Association of hp1181 and hp1184 Genes With the Active Efflux Phenotype in Multidrug-Resistant Isolates of Helicobacter pylori. Jundishapur J Microbiol 2016; 9:e30726. [PMID: 27303615 PMCID: PMC4902859 DOI: 10.5812/jjm.30726] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/14/2015] [Revised: 10/29/2015] [Accepted: 12/23/2015] [Indexed: 02/07/2023] Open
Abstract
BACKGROUND During the last decades the rate of multidrug resistance among clinical Helicobacter pylori isolates has increased. Active pumping out of the drugs may be an important mechanism for multidrug resistance in H. pylori strains. OBJECTIVES The aim of this study was to evaluate the association of two H. pylori efflux-genes, hp1181 and hp1184 with the active-efflux phenotype in MDR clinical-strains of H. pylori. MATERIALS AND METHODS Minimal inhibitory concentration (MIC) and drug accumulation for β-lactames, Tetracycline (TET), Erythromycin (ERY), Metronidazole (MTZ), Ciprofloxacin (CIP) and Ethidium Bromide (EtBr) was performed in the presence and absence of carbonyl cyanide M-Chlorophenyl Hydrazone (CCCP). Presence of hp1181 and hp1184 genes was detected by the polymerase chain reaction (PCR). RT-PCR was performed to compare expression of efflux genes by MDR strains, demonstrating active efflux with the strains without active efflux. RESULTS Two- to four-fold decrease in minimum inhibitory concentration (MIC) and two-fold increase in accumulation were observed for EtBr in the presence of CCCP for 67% (8) of 12 MDR strains. With CCCP, two- to four-fold decrease in MIC and 1.4- to 1.8-fold increase in the accumulation of β-lactames, TET, CIP and MTZ were obtained for 42% (5) of the MDR strains. Six, five and three of the 12 MDR strains amplified hp1184, hp1181, and both of them, respectively. The RT-PCR product for expression of hp1181 by MDR strains was approximately 100 bp shorter than that of the 26695 susceptible standard strain. CONCLUSIONS Expression of the genes hp1184 and hp1181 are associated with the specific active efflux of EtBr and non-related antibiotics, respectively. For displaying these phenotypes, a post-transcriptional regulation step may be required.
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Affiliation(s)
- Tahereh Falsafi
- Depatment of Microbiology, Faculty of Biological Sciences, Alzahra University, Tehran, IR Iran
| | - Azadeh Ehsani
- Depatment of Microbiology, Faculty of Biological Sciences, Alzahra University, Tehran, IR Iran
| | - Bahareh Attaran
- Depatment of Microbiology, Faculty of Biological Sciences, Alzahra University, Tehran, IR Iran
| | - Vahid Niknam
- School of Biology, Tehran University, Tehran, IR Iran
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Li XZ, Plésiat P, Nikaido H. The challenge of efflux-mediated antibiotic resistance in Gram-negative bacteria. Clin Microbiol Rev 2015; 28:337-418. [PMID: 25788514 PMCID: PMC4402952 DOI: 10.1128/cmr.00117-14] [Citation(s) in RCA: 1005] [Impact Index Per Article: 100.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/18/2023] Open
Abstract
The global emergence of multidrug-resistant Gram-negative bacteria is a growing threat to antibiotic therapy. The chromosomally encoded drug efflux mechanisms that are ubiquitous in these bacteria greatly contribute to antibiotic resistance and present a major challenge for antibiotic development. Multidrug pumps, particularly those represented by the clinically relevant AcrAB-TolC and Mex pumps of the resistance-nodulation-division (RND) superfamily, not only mediate intrinsic and acquired multidrug resistance (MDR) but also are involved in other functions, including the bacterial stress response and pathogenicity. Additionally, efflux pumps interact synergistically with other resistance mechanisms (e.g., with the outer membrane permeability barrier) to increase resistance levels. Since the discovery of RND pumps in the early 1990s, remarkable scientific and technological advances have allowed for an in-depth understanding of the structural and biochemical basis, substrate profiles, molecular regulation, and inhibition of MDR pumps. However, the development of clinically useful efflux pump inhibitors and/or new antibiotics that can bypass pump effects continues to be a challenge. Plasmid-borne efflux pump genes (including those for RND pumps) have increasingly been identified. This article highlights the recent progress obtained for organisms of clinical significance, together with methodological considerations for the characterization of MDR pumps.
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Affiliation(s)
- Xian-Zhi Li
- Human Safety Division, Veterinary Drugs Directorate, Health Products and Food Branch, Health Canada, Ottawa, Ontario, Canada
| | - Patrick Plésiat
- Laboratoire de Bactériologie, Faculté de Médecine-Pharmacie, Centre Hospitalier Régional Universitaire, Université de Franche-Comté, Besançon, France
| | - Hiroshi Nikaido
- Department of Molecular and Cell Biology, University of California, Berkeley, California, USA
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Pyridodiazepine amines are selective therapeutic agents for helicobacter pylori by suppressing growth through inhibition of glutamate racemase but are predicted to require continuous elevated levels in plasma to achieve clinical efficacy. Antimicrob Agents Chemother 2015; 59:2337-42. [PMID: 25645840 DOI: 10.1128/aac.04410-14] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/09/2023] Open
Abstract
A pyridodiazepine amine inhibitor of Helicobacter pylori glutamate racemase (MurI) was characterized. The compound was selectively active against H. pylori, and growth suppression was shown to be mediated through the inhibition of MurI by several methods. In killing kinetics experiments, the compound showed concentration-independent activity, with about a 2-log loss of viability in 24 h. A demonstration of efficacy in a mouse infection model was attempted but not achieved, and this was attributed to the failure to attain extended exposure levels above the MIC for >95% of the time. This index and magnitude were derived from pharmacokinetic-pharmacodynamic (PK-PD) studies with amoxicillin, another inhibitor of peptidoglycan biosynthesis that showed slow killing kinetics similar to those of the pyridodiazepine amines. These studies indicate that MurI and other enzymes involved in peptidoglycan biosynthesis may be less desirable targets for monotherapy directed against H. pylori if once-a-day dosing is required.
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Nishizawa T, Suzuki H. Mechanisms of Helicobacter pylori antibiotic resistance and molecular testing. Front Mol Biosci 2014; 1:19. [PMID: 25988160 PMCID: PMC4428472 DOI: 10.3389/fmolb.2014.00019] [Citation(s) in RCA: 62] [Impact Index Per Article: 5.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/23/2014] [Accepted: 10/04/2014] [Indexed: 12/14/2022] Open
Abstract
Antibiotic resistance in Helicobacter pylori (H.pylori) is the main factor affecting the efficacy of current treatment methods against infection caused by this organism. The traditional culture methods for testing bacterial susceptibility to antibiotics are expensive and require 10–14 days. Since resistance to clarithromycin, fluoroquinolone, and tetracycline seems to be exclusively caused by specific mutations in a small region of the responsible gene, molecular methods offer an attractive alternative to the above-mentioned techniques. The technique of polymerase chain reaction (PCR) is an accurate and rapid method for the detection of mutations that confer antibiotic resistance. This review highlights the mechanisms of antibiotic resistance in H. pylori and the molecular methods for antibiotic susceptibility testing.
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Affiliation(s)
- Toshihiro Nishizawa
- Division of Gastroenterology and Hepatology, Department of Internal Medicine, Keio University School of Medicine Tokyo, Japan ; Division of Research and Development for Minimally Invasive Treatment, Cancer Center, Keio University School of Medicine Tokyo, Japan
| | - Hidekazu Suzuki
- Division of Gastroenterology and Hepatology, Department of Internal Medicine, Keio University School of Medicine Tokyo, Japan
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23
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Binh TT, Shiota S, Suzuki R, Matsuda M, Trang TTH, Kwon DH, Iwatani S, Yamaoka Y. Discovery of novel mutations for clarithromycin resistance in Helicobacter pylori by using next-generation sequencing. J Antimicrob Chemother 2014; 69:1796-803. [PMID: 24648504 DOI: 10.1093/jac/dku050] [Citation(s) in RCA: 58] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/17/2022] Open
Abstract
OBJECTIVES Resistance to clarithromycin is the most important factor causing failure of Helicobacter pylori eradication. Although clarithromycin resistance is mainly associated with three point mutations in the 23S rRNA genes, it is unclear whether other mutations are associated with this resistance. METHODS Two types of clarithromycin-resistant strains (low- and high-resistance strains) were obtained from clarithromycin-susceptible H. pylori following exposure to low clarithromycin concentrations. The genome sequences were determined with a next-generation sequencer. Natural transformation was used to introduce the candidate mutations into strain 26695. Etest and an agar dilution method were used to determine the MICs. RESULTS High-resistance strains contained the mutation A2143G in the 23S rRNA genes, whereas low-resistance strains did not. There were seven candidate mutations in six genes outside of the 23S rRNA genes. The mutated sequences in hp1048 (infB), hp1314 (rpl22) and the 23S rRNA gene were successfully transformed into strain 26695 and the transformants showed an increased MIC of and low resistance to clarithromycin. The transformants containing a single mutation in infB or rpl22 (either a 9 bp insertion or a 3 bp deletion) or the 23S rRNA gene showed low MICs (0.5, 2.0, 4.0 and 32 mg/L, respectively) while the transformants containing double mutations (mutation in the 23S rRNA genes and mutation in infB or rpl22) showed higher MICs (>256 mg/L). CONCLUSIONS Next-generation sequencing can be a useful tool for screening mutations related to drug resistance. We discovered novel mutations related to clarithromycin resistance in H. pylori (infB and rpl22), which have synergic effects with 23S rRNA resulting in higher MICs.
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Affiliation(s)
- Tran Thanh Binh
- Department of Environmental and Preventive Medicine, Oita University Faculty of Medicine, Oita, Japan Department of Endoscopy, Cho Ray Hospital, Ho Chi Minh, Vietnam
| | - Seiji Shiota
- Department of Environmental and Preventive Medicine, Oita University Faculty of Medicine, Oita, Japan
| | - Rumiko Suzuki
- Department of Environmental and Preventive Medicine, Oita University Faculty of Medicine, Oita, Japan
| | - Miyuki Matsuda
- Department of Environmental and Preventive Medicine, Oita University Faculty of Medicine, Oita, Japan
| | - Tran Thi Huyen Trang
- Department of Environmental and Preventive Medicine, Oita University Faculty of Medicine, Oita, Japan
| | - Dong Hyeon Kwon
- Biology Department, Long Island University, Brooklyn, NY, USA
| | - Shun Iwatani
- Department of Environmental and Preventive Medicine, Oita University Faculty of Medicine, Oita, Japan Department of Medicine-Gastroenterology, Baylor College of Medicine and Michael E. DeBakey Veterans Affairs Medical Center, Houston, TX, USA
| | - Yoshio Yamaoka
- Department of Environmental and Preventive Medicine, Oita University Faculty of Medicine, Oita, Japan Department of Medicine-Gastroenterology, Baylor College of Medicine and Michael E. DeBakey Veterans Affairs Medical Center, Houston, TX, USA
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Falsafi T, Mahboubi M. Helicobacter hepaticus, a new pathogenic species of the Helicobacter genus: Similarities and differences with H. pylori. IRANIAN JOURNAL OF MICROBIOLOGY 2013; 5:185-94. [PMID: 24475322 PMCID: PMC3895553] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Indexed: 11/01/2022]
Abstract
Helicobacter hepaticus was discovered in 1992 as a cause of liver cancer in the A/JCr mouse model. In susceptible mice, infection by H. hepaticus causes chronic gastrointestinal inflammation leading to neoplasia. It can also cause morphological changes in breast-glands leading to neoplasm and adenocarcinoma in mouse models. Studies performed on humans have revealed that H. hepaticus may also be a human pathogen since infection by H. hepaticus can be associated with cholecystitis, cholelithiasis and gallbladder cancer. H. hepaticus is a close relative of H. pylori, but it lacks the major virulence factors of H. pylori including vacoulating cytotoxin A (VacA) and cytotoxin associated gene (cagA). Moreover, SabA, AlpA, and BabA, three important adhesin proteins of H. pylori, are absent in its genome. In contrast, the genome of H. hepaticus contains genes encoding some orthologus virulence factors of Campylobacter jejuni such as cytolethal distending toxin (CDT), and PebI adhesin factor. Other genes including 16S rRNA, 18 KDa immunogenic protein, and urease structural subunits are related to H. pylori. Its genome contains a small island consisting of 71 Kbp named HHGI1, which probably encodes a secretion system type IV (T4SS), and some other virulence factors. As far as the immunogenic antigens are concerned, the lipopolysaccharide (LPS) and flagellin of H. hepaticus are weak stimulants of the immune system, while pro-inflammatory responses are mainly induced by its lipoproteins and most likely by the peptidoglycan. Concerning the multidrug efflux pumps, a homologue of H. pylori TolC, HefA, has been observed in H. hepaticus which contributes to resistance to amoxicillin and bile acids.
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Affiliation(s)
- Tahereh Falsafi
- Corresponding author: Dr. Tahereh Falsafi, Address: Department of Biology, Alzahra University, Vanak, Tehran, Iran. Tel & Fax: +98-21-88058912. E-mail:
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Abstract
The wide use and abuse of antibiotics have led to serious drug resistance of Helicobacter pylori (H. pylori), and strains simultaneously resistant to metronidazole, clarithromycin and amoxicillin have appeared. As a result, the rate of H. pylori eradication declines clinically. The presence of bacterial efflux pumps is an important mechanism responsible for bacterial resistance to most antibiotics, especially multiple drug resistance (MDR). In recent years, much attention has been paid to the research of efflux pumps and their inhibitors to solve the problem of drug resistance of H. pylori. In this paper we will introduce main efflux pumps and efflux pump inhibitors in H. pylori.
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Lee JW, Kim N, Kim JM, Nam RH, Chang H, Kim JY, Shin CM, Park YS, Lee DH, Jung HC. Prevalence of primary and secondary antimicrobial resistance of Helicobacter pylori in Korea from 2003 through 2012. Helicobacter 2013; 18:206-14. [PMID: 23241101 DOI: 10.1111/hel.12031] [Citation(s) in RCA: 168] [Impact Index Per Article: 14.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/14/2022]
Abstract
BACKGROUND Antimicrobial resistance of Helicobacter pylori (H. pylori) affects the efficacy of eradication therapy. The aim of this study was to estimate the prevalence of primary and secondary resistance of H. pylori isolates to antibiotics and to characterize the risk factors associated with antimicrobial resistance in Korea. MATERIALS AND METHODS This study was performed during the period of 2003-2012. Primary resistance was evaluated from 347 patients without any history of eradication, and secondary resistance was evaluated in 86 patients from whom H. pylori was cultured after failure of eradication. Minimal inhibitory concentration test was performed for amoxicillin, clarithromycin, metronidazole, tetracycline, azithromycin, levofloxacin, and moxifloxacin using agar dilution method. Primary and secondary resistance rates of H. pylori to 7 antibiotics were evaluated and risk factors for the antibiotic resistance were analyzed. RESULTS Increase in the primary resistance rate was found in amoxicillin (6.3-14.9%, p = .051), clarithromycin (17.2-23.7%, p = .323), and both of levofloxacin and moxifloxacin (4.7-28.1%, p = .002) during the study period. Secondary resistance rate significantly increased in metronidazole, levofloxacin, and moxifloxacin. Increase of resistance occurred after initial failure of eradication therapy in case of clarithromycin (p < .001), azithromycin (p < .001), levofloxacin (p = .011), and moxifloxacin (p = .020). Multivariable analyses showed that clarithromycin, azithromycin, levofloxacin, and moxifloxacin resistance was associated with previous eradication treatment history. CONCLUSIONS The increased primary and secondary antibiotic resistance of H. pylori in Korea is ongoing, and it will become a significant limitation for effective eradication of H. pylori in the future.
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Affiliation(s)
- Jung Won Lee
- Department of Internal Medicine, Seoul National University Bundang Hospital, Seongnam, Gyeonggi-do, Korea
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Alvarez-Ortega C, Olivares J, Martínez JL. RND multidrug efflux pumps: what are they good for? Front Microbiol 2013; 4:7. [PMID: 23386844 PMCID: PMC3564043 DOI: 10.3389/fmicb.2013.00007] [Citation(s) in RCA: 135] [Impact Index Per Article: 11.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/13/2012] [Accepted: 01/07/2013] [Indexed: 01/27/2023] Open
Abstract
Multidrug efflux pumps are chromosomally encoded genetic elements capable of mediating resistance to toxic compounds in several life forms. In bacteria, these elements are involved in intrinsic and acquired resistance to antibiotics. Unlike other well-known horizontally acquired antibiotic resistance determinants, genes encoding for multidrug efflux pumps belong to the core of bacterial genomes and thus have evolved over millions of years. The selective pressure stemming from the use of antibiotics to treat bacterial infections is relatively recent in evolutionary terms. Therefore, it is unlikely that these elements have evolved in response to antibiotics. In the last years, several studies have identified numerous functions for efflux pumps that go beyond antibiotic extrusion. In this review we present some examples of these functions that range from bacterial interactions with plant or animal hosts, to the detoxification of metabolic intermediates or the maintenance of cellular homeostasis.
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Affiliation(s)
- Carolina Alvarez-Ortega
- Departamento de Biotecnología Microbiana, Centro Nacional de Biotecnología, Consejo Superior de Investigaciones Científicas Madrid, Spain
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Basarab GS, Hill P, Eyermann CJ, Gowravaram M, Käck H, Osimoni E. Design of inhibitors of Helicobacter pylori glutamate racemase as selective antibacterial agents: Incorporation of imidazoles onto a core pyrazolopyrimidinedione scaffold to improve bioavailabilty. Bioorg Med Chem Lett 2012; 22:5600-7. [DOI: 10.1016/j.bmcl.2012.07.004] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/03/2012] [Revised: 06/28/2012] [Accepted: 07/02/2012] [Indexed: 12/21/2022]
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Francesco VD, Zullo A, Hassan C, Giorgio F, Rosania R, Ierardi E. Mechanisms of Helicobacter pylori antibiotic resistance: An updated appraisal. World J Gastrointest Pathophysiol 2011; 2:35-41. [PMID: 21860834 PMCID: PMC3158889 DOI: 10.4291/wjgp.v2.i3.35] [Citation(s) in RCA: 103] [Impact Index Per Article: 7.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/18/2011] [Revised: 05/29/2011] [Accepted: 06/05/2011] [Indexed: 02/06/2023] Open
Abstract
Helicobacter pylori (H. pylori) antibiotic resistance is the main factor affecting the efficacy of the current eradicating therapies. The aim of this editorial is to report on the recent information about the mechanisms accounting for the resistance to the different antibiotics currently utilized in H. pylori eradicating treatments. Different mechanisms of resistance to clarithromycin, metronidazole, quinolones, amoxicillin and tetracycline are accurately detailed (point mutations, redox intracellular potential, pump efflux systems, membrane permeability) on the basis of the most recent data available from the literature. The next hope for the future is that by improving the knowledge of resistance mechanisms, the elaboration of rational and efficacious associations for the treatment of the infection will be possible. Another auspicious progress might be the possibility of a cheap, feasible and reliable laboratory test to predict the outcome of a therapeutic scheme.
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Bernarde C, Lehours P, Lasserre JP, Castroviejo M, Bonneu M, Mégraud F, Ménard A. Complexomics study of two Helicobacter pylori strains of two pathological origins: potential targets for vaccine development and new insight in bacteria metabolism. Mol Cell Proteomics 2010; 9:2796-826. [PMID: 20610778 PMCID: PMC3101863 DOI: 10.1074/mcp.m110.001065] [Citation(s) in RCA: 18] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/25/2010] [Indexed: 12/12/2022] Open
Abstract
Helicobacter pylori infection plays a causal role in the development of gastric mucosa-associated lymphoid tissue (MALT) lymphoma (LG-MALT) and duodenal ulcer (DU). Although many virulence factors have been associated with DU, many questions remain unanswered regarding the evolution of the infection toward this exceptional event, LG-MALT. The present study describes and compares the complexome of two H. pylori strains, strain J99 associated with DU and strain B38 associated with LG-MALT, using the two-dimensional blue native/SDS-PAGE method. It was possible to identify 90 different complexes (49 and 41 in the B38 and J99 strains, respectively); 12 of these complexes were common to both strains (seven and five in the membrane and cytoplasm, respectively), reflecting the variability of H. pylori strains. The 44 membrane complexes included numerous outer membrane proteins, such as the major adhesins BabA and SabA retrieved from a complex in the B38 strain, and also proteins from the hor family rarely studied. BabA and BabB adhesins were found to interact independently with HopM/N in the B38 and J99 strains, respectively. The 46 cytosolic complexes essentially comprised proteins involved in H. pylori physiology. Some orphan proteins were retrieved from heterooligomeric complexes, and a function could be proposed for a number of them via the identification of their partners, such as JHP0119, which may be involved in the flagellar function. Overall, this study gave new insights into the membrane and cytoplasm structure, and those which could help in the design of molecules for vaccine and/or antimicrobial agent development are highlighted.
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Affiliation(s)
- Cédric Bernarde
- From ‡INSERM U853, 33076 Bordeaux, France and
- §Laboratoire de Bactériologie
| | - Philippe Lehours
- From ‡INSERM U853, 33076 Bordeaux, France and
- §Laboratoire de Bactériologie
| | - Jean-Paul Lasserre
- From ‡INSERM U853, 33076 Bordeaux, France and
- §Laboratoire de Bactériologie
| | - Michel Castroviejo
- ‖Laboratoire de Microbiologie Cellulaire et Moléculaire et Pathogénicité, UMR CNRS 5234, and
| | - Marc Bonneu
- **Pôle Protéomique, Plateforme Génomique Fonctionnelle, Université Victor Segalen Bordeaux 2, Bordeaux, F 33076 France
| | - Francis Mégraud
- From ‡INSERM U853, 33076 Bordeaux, France and
- §Laboratoire de Bactériologie
| | - Armelle Ménard
- From ‡INSERM U853, 33076 Bordeaux, France and
- §Laboratoire de Bactériologie
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Role of the HefC efflux pump in Helicobacter pylori cholesterol-dependent resistance to ceragenins and bile salts. Infect Immun 2010; 79:88-97. [PMID: 20974830 DOI: 10.1128/iai.00974-09] [Citation(s) in RCA: 41] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/10/2023] Open
Abstract
The human gastric pathogen Helicobacter pylori modifies host cholesterol via glycosylation and incorporates the glycosylated cholesterol into its membrane; however, the benefits of cholesterol to H. pylori are largely unknown. We speculated that cholesterol in the H. pylori membrane might alter the susceptibility of these organisms to membrane-disrupting antibacterial compounds. To test this hypothesis, H. pylori strains were cultured in Ham's F-12 chemically defined medium in the presence or absence of cholesterol. The two cultures were subjected to overnight incubations with serial 2-fold dilutions of 10 bile salts and four ceragenins, which are novel bile salt derivatives that mimic membrane-disrupting activity of antimicrobial peptides. H. pylori cultured with cholesterol was substantially more resistant to seven of the bile salts and three ceragenins than H. pylori cultured without cholesterol. In most cases, these cholesterol-dependent differences ranged from 2 to 7 orders of magnitude; this magnitude depended on concentration of the agent. Cholesterol is modified by glycosylation using Cgt, a cholesteryl glycosyltransferase. Surprisingly, a cgt knockout strain still maintained cholesterol-dependent resistance to bile salts and ceragenins, indicating that cholesterol modification was not involved in resistance. We then tested whether three putative, paralogous inner membrane efflux pumps, HefC, HefF, or HefI, played a role. While HefF and HefI appeared unimportant, HefC was shown to play a critical role in the resistance to bile salts and ceragenins by multiple methods in multiple strain backgrounds. Thus, both cholesterol and the putative bile salt efflux pump HefC play important roles in H. pylori resistance to bile salts and ceragenins.
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Hirata K, Suzuki H, Nishizawa T, Tsugawa H, Muraoka H, Saito Y, Matsuzaki J, Hibi T. Contribution of efflux pumps to clarithromycin resistance in Helicobacter pylori. J Gastroenterol Hepatol 2010; 25 Suppl 1:S75-9. [PMID: 20586871 DOI: 10.1111/j.1440-1746.2009.06220.x] [Citation(s) in RCA: 84] [Impact Index Per Article: 5.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/11/2022]
Abstract
BACKGROUND AND AIMS Although clarithromycin (CLR) is one of the most commonly recommended component drugs of Helicobacter pylori eradication regimens, the prevalence of CLR-resistant H. pylori has been increasing. It is well known that CLR resistance is associated with point mutations in 23S rRNA, but an active multidrug efflux mechanism of H. pylori may also play a role in its drug resistance. At least four gene clusters have been identified as efflux pump systems in H. pylori and the present study was designed to investigate their role in the CLR resistance of clinical isolates of H. pylori. METHODS Fifteen CLR-resistant H. pylori strains (minimal inhibitory concentration [MIC]>or= 1 microg/mL) isolated from patients at Keio University Hospital were examined for expression of efflux pump mRNA by real-time polymerase chain reaction. In addition, the MIC of CLR in the presence or absence of Phe-Arg-beta-naphthylamide (PAbetaN), an efflux pump inhibitor (EPI), were determined. RESULTS In all 15 strains, efflux pump mRNA was expressed, and the MIC of CLR were decreased by using EPI, despite possessing 23s rRNA point mutations. In addition, the MIC of CLR was decreased by the EPI in a concentration-dependent fashion. CONCLUSION The efflux pump of H. pylori is associated with the development of resistance to CLR, in addition to 23S rRNA point mutations. Efflux pumps could be a novel target for reversing drug resistance in H. pylori.
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Affiliation(s)
- Kenro Hirata
- Division of Gastroenterology and Hepatology, Department of Internal Medicine, Keio University School of Medicine, Tokyo, Japan
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Zhang Z, Liu ZQ, Zheng PY, Tang FA, Yang PC. Influence of efflux pump inhibitors on the multidrug resistance of Helicobacter pylori. World J Gastroenterol 2010; 16:1279-84. [PMID: 20222174 PMCID: PMC2839183 DOI: 10.3748/wjg.v16.i10.1279] [Citation(s) in RCA: 61] [Impact Index Per Article: 4.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/06/2023] Open
Abstract
AIM: To evaluate the effect of efflux pump inhibitors (EPIs) on multidrug resistance of Helicobacter pylori (H. pylori).
METHODS: H. pylori strains were isolated and cultured on Brucella agar plates with 10% sheep’s blood. The multidrug resistant (MDR) H. pylori were obtained with the inducer chloramphenicol by repeated doubling of the concentration until no colony was seen, then the susceptibilities of the MDR strains and their parents to 9 antibiotics were assessed with agar dilution tests. The present study included periods before and after the advent of the EPIs, carbonyl cyanide m-chlorophenyl hydrazone (CCCP), reserpine and pantoprazole), and the minimum inhibitory concentrations (MICs) were determined accordingly. In the same way, the effects of 5 proton pump inhibitors (PPIs), used in treatment of H. pylori infection, on MICs of antibiotics were evaluated.
RESULTS: Four strains of MDR H. pylori were induced successfully, and the antibiotic susceptibilities of MDR strains were partly restored by CCCP and pantoprazole, but there was little effect of reserpine. Rabeprazole was the most effective of the 5 PPIs which could decrease the MICs of antibiotics for MDR H. pylori significantly.
CONCLUSION: In vitro, some EPIs can strengthen the activities of different antibiotics which are the putative substrates of the efflux pump system in H. pylori.
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Zhang Z, Liu ZQ, Zheng PY, Tang FA. Effects of efflux pump inhibitors on the multidrug resistance of Helicobacter pylori. Shijie Huaren Xiaohua Zazhi 2010; 18:262-267. [DOI: 10.11569/wcjd.v18.i3.262] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/06/2023] Open
Abstract
AIM: To evaluate the effects of efflux pump inhibitors (EPIs) on the multidrug resistance (MDR) of Helicobacter pylori
(H.pylori).
METHODS: H.pylori strains were isolated and cultured on Brucella agar plates containing 10% sheep blood. The MDR of H.pylori strains was induced with chloramphenicol. The susceptibility of multidrug-resistant H.pylori strains and their parental strains to nine antibiotics was assessed by agar dilution test in the presence and absence of EPIs such as CCCP, reserpine and pantoprazole. The minimal inhibitory concentrations (MICs) of different antibiotics against multidrug-resistant H.pylori strains were determined. Similarly, the impact of five proton pump inhibitors (PPIs) on the MICs of these antibiotics was also tested and compared.
RESULTS: Four multidrug-resistant H.pylori strains were induced successfully. The susceptibility of these multidrug-resistant strains to some antibiotics such as cefotaxime were partly restored by CCCP and pantoprazole, but not by reserpine. Of the five PPIs tested, rabeprazole reduced the MICs of metronidazole and amoxicillin against multidrug-resistant H.pylori strains to one forth and one third, respectively, pantoprazole reduced both of them to one half, and the remaining two PPIs showed no obvious effects.
CONCLUSION: Some EPIs can potentiate the activity of antibiotics that are putative substrates of the efflux pump system of H.pylori. Of all PPIs tested, rabeprazole is the most effective one to reduce the MDR of H.pylori.
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Falsafi T, Ehsani A, Niknam V. THE ROLE OF ACTIVE EFFLUX IN ANTIBIOTIC-RESISTANCE OF CLINICAL ISOLATES OF HELICOBACTER PYLORI. Indian J Med Microbiol 2009; 27:335-40. [DOI: 10.4103/0255-0857.55452] [Citation(s) in RCA: 12] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/23/2022]
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Tseng YS, Wu DC, Chang CY, Kuo CH, Yang YC, Jan CM, Su YC, Kuo FC, Chang LL. Amoxicillin resistance with beta-lactamase production in Helicobacter pylori. Eur J Clin Invest 2009; 39:807-12. [PMID: 19614952 DOI: 10.1111/j.1365-2362.2009.02166.x] [Citation(s) in RCA: 35] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/11/2022]
Abstract
BACKGROUND Amoxicillin-resistant Helicobacter pylori with minimal inhibitory concentration (MIC) >or= 256 mg L(-1) was isolated from a gastritis patient. The aims were to investigate the mechanism of high-level amoxicillin resistance in H. pylori. MATERIALS AND METHODS The beta-lactamase production was determined by means of nitrocefin sticks and the presence of gene encoding the beta-lactam antibiotic resistance enzyme TEM beta-lactamase was analysed by polymerase chain reaction (PCR), sequencing and dot-blot hybridization. Sequencing analysis of pbp1A gene was performed and amoxicillin-susceptible isolate was transformed with pbp1A PCR products from the resistant isolate. The expression of hefC efflux system was analysed using real-time quantitative PCR. RESULTS Activity of beta-lactamase was detected. Sequence analysis showed that the PCR product derived from H. pylori 3778 was identical to the bla(TEM-1) (GenBank accession EU726527). Dot-blot hybridization confirmed the presence of beta-lactamase gene bla(TEM-1.) By transformation of PCR product of mutated pbp1A gene from H. pylori 3778 into amoxicillin-susceptible strain showed that substitutions in Thr(556)-->Ser, Lys(648)-->Gln, Arg(649)-->Lys and Arg(656)-->Pro contribute to low-level amoxicillin resistance. The MIC of amoxicillin for the transformants was 0.75 mg L(-1). Over-expression of hefC was not found. CONCLUSIONS High-level amoxicillin resistance is associated with beta-lactamase production in H. pylori. Low-level amoxicillin resistance is linked to a point mutation on pbp1A. Because H. pylori can exchange DNA through natural transformation, spreading of bla(TEM-1) amoxicillin resistance gene among H. pylori is a potential threat when treating H. pylori infection.
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Affiliation(s)
- Y-S Tseng
- Department of Microbiology, Kaohsiung Medical University, Kaohsiung, Taiwan
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Abstract
Drug efflux pumps play a key role in drug resistance and also serve other functions in bacteria. There has been a growing list of multidrug and drug-specific efflux pumps characterized from bacteria of human, animal, plant and environmental origins. These pumps are mostly encoded on the chromosome, although they can also be plasmid-encoded. A previous article in this journal provided a comprehensive review regarding efflux-mediated drug resistance in bacteria. In the past 5 years, significant progress has been achieved in further understanding of drug resistance-related efflux transporters and this review focuses on the latest studies in this field since 2003. This has been demonstrated in multiple aspects that include but are not limited to: further molecular and biochemical characterization of the known drug efflux pumps and identification of novel drug efflux pumps; structural elucidation of the transport mechanisms of drug transporters; regulatory mechanisms of drug efflux pumps; determining the role of the drug efflux pumps in other functions such as stress responses, virulence and cell communication; and development of efflux pump inhibitors. Overall, the multifaceted implications of drug efflux transporters warrant novel strategies to combat multidrug resistance in bacteria.
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Affiliation(s)
- Xian-Zhi Li
- Human Safety Division, Veterinary Drugs Directorate, Health Products and Food Branch, Health Canada, Ottawa, Ontario K1A OK9, Canada
| | - Hiroshi Nikaido
- Department of Molecular and Cell Biology, University of California, Berkeley, California 94720-3202, USA
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de Jonge BLM, Kutschke A, Uria-Nickelsen M, Kamp HD, Mills SD. Pyrazolopyrimidinediones are selective agents for Helicobacter pylori that suppress growth through inhibition of glutamate racemase (MurI). Antimicrob Agents Chemother 2009; 53:3331-6. [PMID: 19433553 PMCID: PMC2715633 DOI: 10.1128/aac.00226-09] [Citation(s) in RCA: 26] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/18/2009] [Revised: 03/21/2009] [Accepted: 05/05/2009] [Indexed: 12/13/2022] Open
Abstract
Pyrazolopyrimidinediones are a novel series of compounds that inhibit growth of Helicobacter pylori specifically. Using a variety of methods, advanced analogues were shown to suppress the growth of H. pylori through the inhibition of glutamate racemase, an essential enzyme in peptidoglycan biosynthesis. The high degree of selectivity of the series for H. pylori makes these compounds attractive candidates for novel H. pylori-selective therapy.
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Affiliation(s)
- B L M de Jonge
- Infection Discovery, Cancer and Infection Research Area, 35 Gatehouse Drive, Waltham, MA 02451, USA.
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Anoushiravani M, Falsafi T, Niknam V. Proton motive force-dependent efflux of tetracycline in clinical isolates of Helicobacter pylori. J Med Microbiol 2009; 58:1309-1313. [PMID: 19574414 DOI: 10.1099/jmm.0.010876-0] [Citation(s) in RCA: 27] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/06/2023] Open
Abstract
The aim of this study was to evaluate the role of proton motive force (PMF)-dependent efflux in resistance of Helicobacter pylori to tetracycline (Tet). Tet MIC was determined by agar dilution in the presence and absence of carbonyl cyanide m-chlorophenylhydrazone (CCCP), an inhibitor of PMF. Antibiotic accumulation was conducted in the presence or absence of CCCP and the fluorescence of the accumulated antibiotic was measured by spectrofluorometry. In the presence of CCCP, antibiotic accumulation was increased by 2-17-fold in 17/20 Tet(r) isolates and by 3-10-fold in four of five high-level-resistant mutants. Correlation was observed between this increase and diminution of MIC with CCCP. PMF-dependent efflux mechanisms therefore appear to play an important role in the resistance of clinical isolates of H. pylori to Tet.
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Affiliation(s)
| | | | - Vahid Niknam
- Department of Biology, Tehran University, Tehran, Iran
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Boyanova L. Prevalence of multidrug-resistant Helicobacter pylori in Bulgaria. J Med Microbiol 2009; 58:930-935. [PMID: 19502370 DOI: 10.1099/jmm.0.009993-0] [Citation(s) in RCA: 36] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/14/2022] Open
Abstract
The aim of this study was to evaluate the presence and prevalence of multidrug antibacterial resistance in Helicobacter pylori in Bulgaria from 2005 to 2008. The resistance in 828 untreated adults, 124 treated adults and 105 untreated children was, respectively, 26.5, 50.8 and 16.2% for metronidazole; 18.4, 45.2 and 19% for clarithromycin; 1, 2.4 and 0% for amoxicillin; 4.4, 10.6 and 1.9% for tetracycline; and 9, 14.5 and 5.8% for ciprofloxacin. Triple resistance to the evaluated agents was uncommon and was detected in 1% of the untreated children, 3.5% of the untreated adults and 13.6% of the treated adults. Five H. pylori strains were resistant to amoxicillin, metronidazole and clarithromycin, two of them exhibiting quadruple resistance. Resistance to four of the five antibacterials tested was found in 0.7% of the untreated and 1.8% of the treated adults. The overall level of multidrug resistance in the treated adults (15.4%) was higher than that in the untreated adults (4.2%, P=0.0001) and the untreated children (1%, P=0.0001). The presence of multidrug H. pylori resistance in Bulgaria could be associated with many factors, among them the slightly increasing national use of macrolides, lincosamides and streptogramins and of quinolones since 2000, the significant increase in primary H. pylori clarithromycin resistance, the high tetracycline use between 1994 and 1999, and, in individual cases, the use of azithromycin-based regimens or reuse of nitroimidazoles. In conclusion, for the first time in a European country during the last 5 years, H. pylori strains harbouring a worrying quadruple antibacterial resistance were found in treated as well as in untreated patients. H. pylori susceptibility patterns have a tendency to become unpredictable and should be monitored constantly at both national and global levels.
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Potent and selective inhibitors of Helicobacter pylori glutamate racemase (MurI): pyridodiazepine amines. Bioorg Med Chem Lett 2008; 19:930-6. [PMID: 19097892 DOI: 10.1016/j.bmcl.2008.11.113] [Citation(s) in RCA: 38] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/26/2008] [Revised: 11/26/2008] [Accepted: 11/26/2008] [Indexed: 12/14/2022]
Abstract
An SAR study of an HTS screening hit generated a series of pyridodiazepine amines as potent inhibitors of Helicobacter pylori glutamate racemase (MurI) showing highly selective anti-H. pylori activity, marked improved solubility, and reduced plasma protein binding. X-ray co-crystal E-I structures were obtained. These uncompetitive inhibitors bind at the MurI dimer interface.
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Khan R, Nahar S, Mukhopadhyay AK, Berg DE, Ahmad MM, Okamoto K, Nair GB, Rahman M. Isolation of tetracycline-resistant clinicalHelicobacter pyloriwithout mutations in 16S rRNA gene in Bangladesh. Microbiol Immunol 2008; 52:508-11. [DOI: 10.1111/j.1348-0421.2008.00062.x] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/21/2022]
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Liu ZQ, Zheng PY, Yang PC. Efflux pump gene hefA of Helicobacter pylori plays an important role in multidrug resistance. World J Gastroenterol 2008; 14:5217-22. [PMID: 18777600 PMCID: PMC2744013 DOI: 10.3748/wjg.14.5217] [Citation(s) in RCA: 66] [Impact Index Per Article: 3.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/06/2023] Open
Abstract
AIM: To determine whether efflux systems contribute to multidrug resistance of H pylori.
METHODS: A chloramphenicol-induced multidrug resistance model of six susceptible H pylori strains (5 isolates and H pylori NCTC11637) was developed. Multidrug-resistant (MDR) strains were selected and the minimal inhibitory concentration (MIC) of erythromycin, metronidazole, penicillin G, tetracycline, and ciprofloxacin in multidrug resistant strains and their parent strains was determined by agar dilution tests. The level of mRNA expression of hefA was assessed by fluorescence real-time quantitative PCR. A H pylori LZ1026 knockout mutant (ΔH pylori LZ1026) for (putative) efflux protein was constructed by inserting the kanamycin resistance cassette from pEGFP-N2 into hefA, and its susceptibility profiles to 10 antibiotics were evaluated.
RESULTS: The MIC of six multidrug-resistant strains (including 5 clinical isolates and H pylori NCTC11637) increased significantly (≥ 4-fold) compared with their parent strains. The expression level of hefA gene was significantly higher in the MDR strains than in their parent strains (P = 0.033). A H pylori LZ1026 mutant was successfully constructed and the ΔH pylori LZ1026 was more susceptible to four of the 10 antibiotics. All the 20 strains displayed transcripts for hefA that confirmed the in vitro expression of these genes.
CONCLUSION: The efflux pump gene hefA plays an important role in multidrug resistance of H pylori.
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Jones KR, Cha JH, Merrell DS. Who's Winning the War? Molecular Mechanisms of Antibiotic Resistance in Helicobacter pylori. CURRENT DRUG THERAPY 2008; 3:190-203. [PMID: 21765819 DOI: 10.2174/157488508785747899] [Citation(s) in RCA: 28] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/06/2023]
Abstract
The ability of clinicians to wage an effective war against many bacterial infections is increasingly being hampered by skyrocketing rates of antibiotic resistance. Indeed, antibiotic resistance is a significant problem for treatment of diseases caused by virtually all known infectious bacteria. The gastric pathogen Helicobacter pylori is no exception to this rule. With more than 50% of the world's population infected, H. pylori exacts a tremendous medical burden and represents an interesting paradigm for cancer development; it is the only bacterium that is currently recognized as a carcinogen. It is now firmly established that H. pylori infection is associated with diseases such as gastritis, peptic and duodenal ulceration and two forms of gastric cancer, gastric adenocarcinoma and mucosa-associated lymphoid tissue (MALT) lymphoma. With such a large percentage of the population infected, increasing rates of antibiotic resistance are particularly vexing for a treatment regime that is already fairly complicated; treatment consists of two antibiotics and a proton pump inhibitor. To date, resistance has been found to all primary and secondary lines of antibiotic treatment as well as to drugs used for rescue therapy.
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Affiliation(s)
- Kathleen R Jones
- Department of Microbiology and Immunology, Uniformed Services University of the Health Sciences, 4301 Jones Bridge Rd., Bethesda, MD 20814, USA
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Design of Helicobacter pylori glutamate racemase inhibitors as selective antibacterial agents: A novel pro-drug approach to increase exposure. Bioorg Med Chem Lett 2008; 18:4716-22. [DOI: 10.1016/j.bmcl.2008.06.092] [Citation(s) in RCA: 30] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/30/2008] [Revised: 06/26/2008] [Accepted: 06/26/2008] [Indexed: 11/17/2022]
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Abstract
Eradication therapy for Helicobacter pylori is recommended in a number of clinical conditions. In this article, we discuss the epidemiology and cellular mechanisms that result in antimicrobial resistance, the results of current eradication therapies, and new approaches to the management of Helicobacter pylori infection.
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Affiliation(s)
- Nimish Vakil
- Department of Medicine, University of Wisconsin School of Medicine and Public Health, Madison, Wisconsin, USA.
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Mégraud F, Lehours P. Helicobacter pylori detection and antimicrobial susceptibility testing. Clin Microbiol Rev 2007; 20:280-322. [PMID: 17428887 PMCID: PMC1865594 DOI: 10.1128/cmr.00033-06] [Citation(s) in RCA: 482] [Impact Index Per Article: 26.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/06/2023] Open
Abstract
The discovery of Helicobacter pylori in 1982 was the starting point of a revolution concerning the concepts and management of gastroduodenal diseases. It is now well accepted that the most common stomach disease, peptic ulcer disease, is an infectious disease, and all consensus conferences agree that the causative agent, H. pylori, must be treated with antibiotics. Furthermore, the concept emerged that this bacterium could be the trigger of various malignant diseases of the stomach, and it is now a model for chronic bacterial infections causing cancer. Most of the many different techniques involved in diagnosis of H. pylori infection are performed in clinical microbiology laboratories. The aim of this article is to review the current status of these methods and their application, highlighting the important progress which has been made in the past decade. Both invasive and noninvasive techniques will be reviewed.
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Affiliation(s)
- Francis Mégraud
- INSERM U853, and Université Victor Segalen Bordeaux 2, and Laboratoire de Bactériologie, Hôpital Pellegrin, Place Amélie Raba-Léon, 33076 Bordeaux cedex, France.
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Nishizawa T, Suzuki H, Kurabayashi K, Masaoka T, Muraoka H, Mori M, Iwasaki E, Kobayashi I, Hibi T. Gatifloxacin resistance and mutations in gyra after unsuccessful Helicobacter pylori eradication in Japan. Antimicrob Agents Chemother 2006; 50:1538-40. [PMID: 16569878 PMCID: PMC1426923 DOI: 10.1128/aac.50.4.1538-1540.2006] [Citation(s) in RCA: 46] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/20/2022] Open
Abstract
A high resistance rate (47.9%) to gatifloxacin (GAT; 8-methoxy fluoroquinolone) in Helicobacter pylori (H. pylori) strains from 48 Japanese patients is observed after unsuccessful H. pylori eradication. A significant association between MICs for GAT equal to or above 1 microg/ml and mutations of the gyrA gene of H. pylori was demonstrated.
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Affiliation(s)
- Toshihiro Nishizawa
- Department of Internal Medicine, Keio University School of Medicine, and Department of Gastroenterology, Kitasato Institute Hospital, 35 Shinanomachi, Shinjuku-ku, Tokyo 160-8582, Japan
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