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: 8870876
• 负责人: DOUGLAS R. CALL
• 金额: $ 22.65万
• 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 2017-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8870876
• 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; public health relevance; 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（由应用提供）：抗菌抗性（AMR）是对全球卫生安全和一项健康挑战的重大威胁，因为人类和动物医学​​中的抗生素使用都有助于AMR细菌的出现，扩增，持久和传播。当前对AMR的控制主要依赖于审慎的使用原理和监管控制，以及替代抗生素和感染控制措施的发展。但是，限制抗生素使用仅与现有AMR种群有关，如果与AMR特征携带者相关的大量拟合成本。在实践中，这种被动衰变机制在很大程度上是无效的，因为携带抵抗性状的健身成本很低。该项目将制定一种完全新颖的策略，可以人为地诱导针对AMR细菌的高健身成本，并将这些微生物从某些人群中驱逐出来。重点将是四环素外排泵，仅在四环素抗生素存在下表达。它可以通过将细菌暴露于不会损害四环素敏感细菌的降解的四环素中来诱导TET（A）和TET（B）衰减泵的表达。众所周知，在辅助因子存在下表达这些衰老泵的组合可以对耐四环素抗性细菌施加显着的适应性成本，但是这个想法从未扩展到人口级的控制。该项目将检验一个中心假设，即在存在特定辅助因子的情况下，四环素抗性外排泵的表达将对宿主细菌施加显着的适应性成本，并且可以探索该机制以降低抗生素耐药菌的流行。通过一系列基于实验室和现场的实验，该项目试图（1）确定是否可以将主动选择推广到其他四环素外排泵和细菌病原体。该目标将识别辅助因子，估计不同四环素耐药细菌的响应方差，并确定负责诱导四环素表达的降解四环素的成分。 （2）确定口服改性四环素产物（没有辅助因子的R）是否可以降低动物模型中多药耐多层大肠杆菌的患病率。此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以将其传播给人的AMR种群。 （3）确定添加有或没有辅助因子的修饰四环素是否可以降低土壤储层中发现的抗性大肠杆菌的患病率。 AMR细菌的水库可能在长期中起重要作用 这些细菌在环境中的持久性。如果我们能够通过主动选择选择性地靶向主要储量，这将降低食物链中AMR细菌的总体患病率，并在包括医院在内的其他环境中可能降低。使用对AMR细菌进行主动选择是完全新颖且创新的，与依赖被动下降相比，AMR细菌的迅速丧失。它还具有离开细菌的抗生素爆发群体的优势，因此很大程度上不受影响 植物群。