Tetracycline resistance: the Achilles' heel of antibiotic resistance?

四环素耐药性：抗生素耐药性的致命弱点？

• 批准号: 9098591
• 负责人: DOUGLAS R. CALL
• 金额: $ 18.88万
• 依托单位: WASHINGTON STATE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2015
• 资助国家: 美国
• 起止时间: 2015-07-01 至 2018-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9098591
• 关键词: Animal Feed; Animal Model; Animals; Anti-Bacterial Agents; Antibiotic Resistance; Antibiotics; Antimicrobial Resistance; Bacteria; Binding; Cells; Centers for Disease Control and Prevention (U.S.); Cessation of life; Chelating Agents; Chickens; DNA; Data; Development; Environment; Escherichia coli; Exposure to; Face; Food Chain; Genes; Genetic Transcription; Growth; Health; Hospitals; Human; Infection; Infection Control; Infectious Agent; Left; Link; Measures; Medicine; Microbe; Modeling; Multi-Drug Resistance; Oral Administration; Oxytetracycline; Play; Population; Prevalence; Promoter Regions; Race; Repressor Proteins; Resistance; Role; Security; Series; Soil; Surveys; Testing; Tetanus Helper Peptide; Tetracycline Resistance; Tetracyclines; Time; Variant; Work; arm; base; cofactor; cost; efflux pump; fighting; fitness; global health; innovation; microbial; novel; novel strategies; pathogen; research study; resistance gene; resistant strain; response; trait

 DESCRIPTION (provided by applicant): Antimicrobial resistance (AMR) is a significant threat to global health security and a one-health challenge because antibiotic use in both human and animal medicine contributes to the emergence, amplification, persistence and dissemination of AMR bacteria. Control of AMR currently relies primarily on prudent use principles and regulatory controls and on development of alternative antibiotics and infection control measures. However, limiting antibiotic use only works against existing AMR populations if there is a significant fitnes cost associated with carriage of AMR traits. In practice, this PASSIVE decay mechanism is largely ineffective because fitness costs for harboring resistance traits are low. This project wil develop a completely novel strategy to artificially induce a high fitness cost against AMR bacteria and ACTIVELY drive these microbes out of select populations. The focus will be tetracycline efflux pumps that are only expressed in the presence of a tetracycline antibiotic. It s possible to induce expression of tet(A) and tet(B) efflux pumps by exposing the bacteria to a degraded tetracycline that does not harm tetracycline-sensitive bacteria. A combination of expressing these efflux pumps in the presence of cofactors is known to impose a significant fitness cost on the tetracycline-resistant bacteria, but this idea has never been extended to population-level control. This project will test the central hypothesis that in the presence of specific cofactors, expression of tetracycline-resistance efflux pumps will impose a significant fitness cost on the host bacterium and this mechanism can be exploited to reduce the prevalence of antibiotic-resistant bacteria. With a series of lab-based and field-based experiments, this project seeks to (1) Determine if active selection can be generalized to additional tetracycline efflux pumps and to bacterial pathogens. This aim will identify cofactors, estimate the variance of the response by different tetracycline-resistant bacteria, and identify th component of the degraded tetracycline that is responsible for inducing expression of tetracycline efflux. (2) Determine if oral administration of a modified tetracycline product, with r without a cofactor, can reduce the prevalence of multidrug resistant E. coli in an animal model. This aim will employ a chicken model to determine if active selection can be used to limit AMR populations that could otherwise be disseminated to people. (3) Determine if addition of a modified tetracycline, with or without a cofactor, can reduce the prevalence of resistant E. coli found in soil reservoirs. Reservoirs of AMR bacteria likely play an important role in the long-term persistence of these bacteria in the environment. If we are able to selectively target primary reservoirs by active selection, this will reduce the overall prevalence of AMR bacteria in food chain and possibly in other environments including hospitals. Employing active selection against AMR bacteria is completely novel and innovative, and will result in rapid loss of AMR bacteria as compared to reliance on passive decline. It also has the advantage of leaving the antibiotic-susceptible population of bacteria largely unaffected and thus limit disruption of normal microbial flora.

 描述（由申请人提供）：抗菌素耐药性（AMR）是对全球卫生安全的重大威胁，也是一项单一健康挑战，因为人类和动物医学中的抗生素使用有助于AMR细菌的出现、扩增、持续和传播。AMR的控制目前主要依赖于谨慎使用原则和监管控制以及替代抗生素和感染控制措施的开发。然而，限制抗生素的使用只对现有的AMR人群有效，如果有一个显着的fitnes成本与AMR性状的携带相关。在实践中，这种被动衰减机制在很大程度上是无效的，因为携带抗性性状的适应性成本很低。该项目将开发一种全新的策略，人工诱导对AMR细菌的高适应性成本，并主动将这些微生物赶出选定的种群。重点将是四环素外排泵，仅在四环素抗生素存在下表达。通过将细菌暴露于不伤害四环素敏感细菌的降解四环素，可以诱导泰特（A）和泰特（B）外排泵的表达。已知在辅因子的存在下表达这些外排泵的组合对四环素抗性细菌施加显著的适应性成本，但这种想法从未扩展到群体水平的控制。该项目将测试中心假设，即在特定辅因子的存在下，四环素抗性外排泵的表达将对宿主细菌施加显著的适应性成本，并且可以利用这种机制来减少耐药细菌的流行。通过一系列基于实验室和现场的实验，本项目旨在（1）确定主动选择是否可以推广到额外的四环素外排泵和细菌病原体。这一目标将确定辅因子，估计不同的四环素耐药细菌的反应的方差，并确定降解四环素的组分，负责诱导四环素外排的表达。(2)确定口服一种改良的四环素产品（含r，不含辅因子）是否能降低多药耐药大肠杆菌的流行。在动物模型中。这一目标将采用鸡模型来确定是否可以使用主动选择来限制可能传播给人类的AMR种群。(3)确定添加修饰的四环素（含或不含辅因子）是否能降低耐药大肠杆菌的流行。在土壤水库中发现的大肠杆菌。AMR细菌库可能在长期内发挥重要作用 这些细菌在环境中的持久性。如果我们能够通过主动选择来选择性地靶向主要宿主，这将降低AMR细菌在食物链中的总体流行率，并可能在包括医院在内的其他环境中。采用针对AMR细菌的主动选择是完全新颖和创新的，与依赖被动下降相比，将导致AMR细菌的快速损失。它还具有使细菌的嗜水气单胞菌易感群体在很大程度上不受影响的优点，从而限制了正常微生物的破坏。 植物群。