Host factors required for vancomycin resistance in enterococci

项目摘要 抗生素耐药性的持续和不可避免的出现需要一个强有力的和持续的 努力从根本上确定新的目标和创新的抗菌治疗策略。 抗生素耐药肠球菌，如万古霉素耐药肠球菌（VRE）是导致肠球菌感染的主要原因。 医院获得性感染，很少有好的治疗选择来治疗VRE感染。一 关于万古霉素耐药性的遗传和生化机制， 由水平获得的vanA和vanB基因簇提供，它们重新编程天然的 肠球菌肽聚糖合成途径以产生和使用肽聚糖前体 在肽侧的末端位置含有D-乳酸（而不是天然的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。 肽聚糖合成途径，以成功地建立必要的肽聚糖，但作用 肠球菌宿主因子在介导万古霉素耐药性方面知之甚少。我们的数据表明 核心肠球菌基因组中编码的宿主因子实际上是表型 水平获得的货车基因簇赋予万古霉素耐药性。尤其是细胞壁 称为CroS/R的应力传感系统响应VRE中万古霉素诱导的细胞壁应力， 驱动万古霉素耐药所必需的宿主肠球菌基因的转录。第一主 必须克服的知识差距，以了解肠球菌宿主因素如何驱动 万古霉素耐药性，并随后利用这些因子作为新治疗剂的靶点， 使VRE对万古霉素敏感，是（i）鉴定特异性CoS/R依赖性肠球菌宿主 万古霉素耐药所需的因素;和（ii）证明交叉/R依赖性 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。的 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 新的治疗方法，使万古霉素耐药性消失，并增强万古霉素的活性， 反对VRE。

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.