New understanding of LTA as a determinant of daptomycin susceptibility in VRE E. faecium

对 LTA 作为 VRE 屎肠球菌达托霉素敏感性决定因素的新认识

• 批准号: 9810471
• 负责人: Michael S Gilmore
• 金额: $ 25.5万
• 依托单位: MASSACHUSETTS EYE AND EAR INFIRMARY
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-05-07 至 2021-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9810471
• 关键词: Anabolism; Antibiotics; Antimicrobial Resistance; Back; Binding; Boston; Cardiolipins; Cell Wall; Cell membrane; Corpus striatum structure; Corynebacterium; Daptomycin; Data; Defect; Enterococcus; Enterococcus faecium; Enzymes; Exhibits; Genes; Genetic Polymorphism; Glycopeptides; Goals; Homologous Gene; Hospitals; Infection; Investigation; Lead; Left; Lesion; Membrane; Modeling; Modification; Multi-Drug Resistance; Mutate; Mutation; Nosocomial Infections; Pathway interactions; Peptidoglycan; Pharmaceutical Preparations; Pharmacotherapy; Phenotype; Phosphatidylglycerols; Phospholipids; Physiological; Postdoctoral Fellow; Predisposition; Production; Research; Resistance; Staphylococcus aureus; Stress; Teichoic Acids; Testing; Urinary tract; Urinary tract infection; Vancomycin Resistance; Vancomycin resistant enterococcus; Work; acronyms; bactericide; base; biological adaptation to stress; cardiolipin synthase; experimental study; gain of function mutation; graduate student; lipoteichoic acid; loss of function mutation; mutant; prevent; resistant strain; response; stem

Project summary: Enterococci are leading causes of multidrug resistant hospital acquired infection – the first E in the ESKAPE acronym. Most E. faecium isolates at major centers are vancomycin resistant (VRE), and daptomycin is often the last line bactericidal drug for treatment. Unfortunately, daptomycin resistance is increasingly common, and can arise during treatment. Here we discovered a new vulnerability of VRE that appears to be related to production of membrane anchored lipoteichoic acid (LTA). A naturally occurring E. faecium mutant in this pathway, isolated from an infected urinary tract, exhibited hypersusceptibility to daptomycin, with a 20-fold lower MIC to this key drug. We developed preliminary data to show that this stemmed from a mutation in a gene termed lafB, which encodes an enzyme that make the immediate precursor glycopeptide onto which LTA is built. When selecting for revertants to the wild type level of daptomycin susceptibility or greater, we observed that lafB was always the first to mutate back, indicating that it may be dominant to other mutations that result in daptomycin resistance. If so, inhibition of lafB would have the potential to undo daptomycin resistance by other mechanisms, or at minimum, prevent those mutations from arising during treatment. The following proposal outlines a rigorous set of experiments to explore this new determinant of daptomycin susceptibility.

项目摘要： 肠球菌是抗多药耐药的医院感染的主要原因 - 第一个E Eskape首字母缩写。主要中心的大多数大肠杆菌分离株是万古霉素耐药（VRE）， daptomycin通常是最后一行的细菌药物进行治疗。不幸的是，达托霉素 耐药性越来越普遍，可以在治疗过程中出现。在这里，我们发现了一个新的 VRE的脆弱性似乎与膜锚定Lipoteichoic的生产有关 酸（LTA）。从感染的 尿路，暴露于daptomycin的超高含量，该关键药物低20倍。 我们开发了初步数据，以表明这是源于称为LAFB的基因中的突变， 它编码使立即前体糖肽在其中LTA所在的酶 建造。当选择恢复到daptomycin易感性或更大的野生型逆转时， 我们观察到LAFB始终是第一个突变的人，表明它可能是主导的 导致二霉素耐药性的其他突变。如果是这样，抑制LAFB将具有 通过其他机制来消除daptomycin耐药性的可能性，或至少防止这些机制 在治疗过程中引起的突变。以下提案概述了一套严格的 探索Daptomycin敏感性的新决定者的实验。