Intrinsic cephalosporin resistance in enterococci

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。 耐药肠球菌是医院获得性感染的主要原因。肠球菌是 成功的医院获得性病原菌部分原因是他们对常用药物的内在抗药性 针对细菌细胞膜的抗生素，如头孢菌素。然而，许多问题 关于肠球菌对头孢菌素耐药的遗传和生化基础仍然存在。 先前的工作揭示了跨膜蛋白激酶(IREK)及其细胞内的关键作用 底物(IreB)参与头孢菌素耐药的调控，但下游效应分子参与信号转导 途径仍不清楚。在初步研究中，我们发现两个UDP-GlcNAc中有一个(Muraa) 粪肠球菌编码的1-羧基乙烯基转移酶(催化肽聚糖的第一步 (生物合成)是头孢菌素耐药所必需的。Muraa(Murab)的对偶 不能引起头孢菌素耐药性。因此，Muraa拥有一种特殊的、特定的能力 促进头孢菌素耐药。需要解决的主要知识差距是：(1)a Irek途径和Muraa之间的生化联系尚未建立，以及(Ii) MuraA驱动头孢菌素耐药性的机制尚不清楚。在这里提出的这项研究 旨在阐明对Muraa在推动 肠球菌头孢菌素耐药。通过这样做，我们将提供对基本的 驱动肠球菌关键抗生素耐药性的生物学过程，并可能定义新的靶点 旨在削弱肠球菌头孢菌素耐药性的创新疗法。

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 are major causes of hospital-acquired infections. Enterococci are successful hospital-acquired pathogens in part because of their intrinsic resistance to commonly used antibiotics that target the bacterial cell envelope, such as cephalosporins. However, many questions remain regarding the genetic and biochemical basis for cephalosporin resistance in enterococci. Previous work revealed a key role for a transmembrane protein kinase (IreK) and its intracellular substrate (IreB) in regulation of cephalosporin resistance, but the downstream effectors in the signaling pathway remain unknown. In preliminary studies we showed that one (MurAA) of two UDP-GlcNAc 1-carboxyvinyltransferases encoded in E. faecalis (catalyzing the first committed step in peptidoglycan biosynthesis) is specifically required for cephalosporin resistance. The paralog of MurAA (MurAB) cannot drive cephalosporin resistance. Hence, MurAA possesses a specialized, specific ability to promote cephalosporin resistance. The major knowledge gaps to be addressed are that (i) a biochemical link between the IreK pathway and MurAA has not been established, and (ii) the mechanism by which MurAA drives cephalosporin resistance is unknown. The research proposed here is designed to elucidate new insights into the role of MurAA in the biological processes that drive enterococcal cephalosporin resistance. By doing so, we will provide new insights into the fundamental biological processes that drive key antibiotic resistance in enterococci and may define new targets for innovative therapeutics designed to impair enterococcal cephalosporin resistance.