Host factors required for vancomycin resistance in enterococci

肠球菌万古霉素耐药所需的宿主因素

• 批准号: 10215113
• 负责人: CHRISTOPHER J KRISTICH
• 金额: $ 19.5万
• 依托单位: MEDICAL COLLEGE OF WISCONSIN
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-02-03 至 2023-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10215113
• 关键词: Alanine; Antibiotic Resistance; Automobile Driving; Bacterial Antibiotic Resistance; Biochemical; Biological Process; Cell Wall; Centers for Disease Control and Prevention (U.S.); Clinical; Data; Development; Enterococcus; Enterococcus faecalis; Enterococcus faecium; Exhibits; Foundations; Funding Mechanisms; Future; Gene Cluster; Genes; Genetic; Genetic Transcription; Genome; Glycopeptide Antibiotics; Goals; Healthcare; Infection; Integration Host Factors; Intervention; Investments; Knowledge; Mediating; Nosocomial Infections; Output; Pathway interactions; Peptides; Peptidoglycan; Phenotype; Positioning Attribute; Proteins; Reporting; Research; Resistance; Role; Side; Signal Pathway; Signal Transduction; Solid; Stress; System; Therapeutic; United States; Vancomycin; Vancomycin Resistance; Vancomycin resistant enterococcus; Work; World Health Organization; antimicrobial; clinically relevant; drug resistant pathogen; emerging antibiotic resistance; genetic approach; genetic testing; genome-wide; inhibitor/antagonist; innovation; insight; methicillin resistant Staphylococcus aureus; mutant; new therapeutic target; novel; novel therapeutics; pathogen; priority pathogen; research and development; response; therapeutic target; treatment response

PROJECT SUMMARY The continued and inevitable emergence of antibiotic resistance demands a vigorous and sustained effort to identify fundamentally new targets and strategies for innovative antimicrobial therapeutics. Antibiotic-resistant enterococci such as vancomycin-resistant enterococci (VRE) are major causes of hospital-acquired infections, and there are few good therapeutic options to treat VRE infections. A great deal is known about the genetic and biochemical mechanisms of vancomycin resistance provided by the horizontally acquired vanA and vanB gene clusters, which reprogram the native enterococcal peptidoglycan synthesis pathway to produce and use peptidoglycan precursors containing D-lactate (instead of the natural D-alanine) at the terminal position of the peptide side chain. These modified precursors must be acted on by multiple proteins in the native enterococcal peptidoglycan synthesis pathway to successfully build the essential peptidoglycan, yet the role of enterococcal host factors in mediating vancomycin resistance is poorly understood. Our data indicate that host factors encoded in the core enterococcal genome are in fact required for phenotypic vancomycin resistance conferred by horizontally acquired van gene clusters. In particular, a cell-wall- stress sensing system known as CroS/R responds to vancomycin-induced cell wall stress in VRE and drives transcription of host enterococcal genes essential for vancomycin resistance. The first major knowledge gaps that must be overcome to understand how enterococcal host factors drive vancomycin resistance, and to subsequently exploit such factors as targets for new therapeutics that sensitize VRE to vancomycin, are (i) to identify the specific CroS/R-dependent enterococcal host factors that are required for vancomycin resistance; and (ii) to demonstrate that CroS/R-dependent host factors are required for vancomycin resistance in all types of clinically relevant VRE. The research proposed here will fill these gaps to establish a solid foundation for the future development of new therapeutics that disable vancomycin resistance and potentiate the activity of vancomycin against VRE.

项目摘要 抗生素耐药性的持续和不可避免的出现需要充满活力和持久 努力从根本上确定创新抗菌治疗剂的新目标和策略。 抗生素耐药的肠球菌，例如万古霉素的肠球菌（VRE）是主要原因 医院可获得的感染，几乎没有治疗VRE感染的好的治疗方法。一个 关于万古霉素耐药性的遗传和生化机制知之甚少 由水平获取的Vana和VanB基因簇提供，它们重新编程 肠球菌肽聚糖合成途径，生产和使用肽聚糖前体 在肽侧的末端位置含有D-乳酸（代替天然D-丙氨酸） 链。这些修饰的前体必须由天然肠球菌中的多种蛋白质作用 肽聚糖的合成途径成功地建立了必不可少的肽聚糖，但是 介导万古霉素耐药性中的肠球菌宿主因素知之甚少。我们的数据表明 实际上，核心肠球菌基因组中编码的宿主因素实际上是表型的 水平获得的范基因簇赋予万古霉素的耐药性。特别是一个细胞壁 称为CROS/R的压力感应系统对VRE和VRE中的VARomycin诱导的细胞壁应力做出反应 驱动宿主肠球菌基因的转录对于万古霉素抗性必不可少的。第一个专业 必须克服必须克服的知识差距，以了解肠球菌宿主因素如何驱动 万古霉素的耐药性，并随后利用诸如新疗法的靶标的因素 将VRE敏感到万古霉素，是（i）识别特定的cros/r依赖性肠宿主 万古霉素耐药性所需的因素； （ii）证明cros/r依赖性 在所有类型的临床相关VRE中，都需要宿主因素才能进行万古霉素耐药性。这 这里提出的研究将填补这些空白，以确立未来发展的坚实基础 新的治疗剂，可禁用万古霉素耐药性并增强万古霉素的活性 反对VRE。