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: 10339472
• 负责人: CHRISTOPHER J KRISTICH
• 金额: $ 23.4万
• 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 2024-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10339472
• 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; 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.

项目总结 抗生素耐药性的持续和不可避免的出现需要强有力和持续的 努力从根本上确定创新抗菌疗法的新目标和战略。 耐抗生素肠球菌，如万古霉素耐药肠球菌(VRE)是引起 医院获得性感染，几乎没有治疗VRE感染的好的治疗选择。一个 人们对万古霉素耐药的遗传和生化机制已有大量了解 由水平获得的Vana和VanB基因簇提供，它们对本机进行重新编程 肠球菌肽聚糖合成途径及其前体的生产和利用 在多肽的末端含有D-乳酸(而不是天然的D-丙氨酸) 链条。这些修饰的前体必须由天然肠球菌中的多种蛋白质作用。 肽聚糖的合成途径是成功构建必需的肽聚糖的，但其作用机制尚不清楚 肠球菌宿主因素在介导万古霉素耐药中的作用尚不清楚。我们的数据显示 编码在核心肠球菌基因组中的宿主因子实际上是表型所必需的 水平获得性van基因簇引起的万古霉素耐药。尤其是细胞壁-- 应力传感系统CROS/R对万古霉素诱导的VRE和VRE细胞壁应力的反应 促进宿主肠球菌基因的转录，这些基因对万古霉素耐药至关重要。第一大调 必须克服的知识差距，以了解肠球菌宿主因素是如何推动 万古霉素耐药，并随后利用这些因素作为新疗法的靶点 使VRE对万古霉素增敏，ARE(I)识别依赖CROS/R的特异性肠球菌宿主 万古霉素耐药所需的因素；以及(Ii)证明CROS/R依赖 在所有类型的临床相关VRE中，宿主因素是万古霉素耐药所必需的。这个 本文提出的研究将填补这些空白，为未来的发展奠定坚实的基础 消除万古霉素耐药性并增强万古霉素活性的新疗法 对阵VRE。