Intrinsic cephalosporin resistance in enterococci

肠球菌的内在头孢菌素耐药性

• 批准号: 9419533
• 负责人: CHRISTOPHER J KRISTICH
• 金额: $ 38.5万
• 依托单位: MEDICAL COLLEGE OF WISCONSIN
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-09-14 至 2022-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9419533
• 关键词: Address; Ampicillin Resistance; Anabolism; Antibiotic Resistance; Antibiotics; Automobile Driving; Bacterial Antibiotic Resistance; Bacterial Genome; Biochemical; Biological Process; Cell Wall; Cell physiology; Cells; Centers for Disease Control and Prevention (U.S.); Cephalosporin Resistance; Cephalosporins; Clinical; Data; Development; Dimerization; Enterococcus; Enterococcus faecalis; Enterococcus faecium; Escherichia coli; Exhibits; Fosfomycin; Foundations; Gene Order; Genes; Genetic; Genome; Healthcare; Hospitals; Impairment; Infection; Integral Membrane Protein; Intervention; Knowledge; Link; Multi-Drug Resistance; N-acetylglucopyranosylamine; Nosocomial Infections; Outcome; Output; Pathway interactions; Penicillin-Binding Proteins; Peptidoglycan; Phosphotransferases; Property; Protein Kinase; Regulation; Reporting; Research; Resistance; Role; Signal Pathway; Therapeutic; Therapeutic Intervention; United States; Vancomycin resistant enterococcus; Variant; Work; antimicrobial; base; cell envelope; clinically relevant; clinically significant; crosslink; design; drug resistant pathogen; in vivo; inhibitor/antagonist; innovation; insight; methicillin resistant Staphylococcus aureus; mutant; new therapeutic target; novel; paralogous gene; pathogen; programs; synergism

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.

项目概要 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 努力确定创新抗菌疗法的全新目标和策略。 耐抗生素肠球菌是医院获得性感染的主要原因。肠球菌是 医院获得性病原体成功的部分原因是它们对常用的病原体具有内在的抵抗力 针对细菌细胞包膜的抗生素，例如头孢菌素。然而很多疑问 关于肠球菌头孢菌素耐药性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) 参与头孢菌素耐药性的调节，但下游效应子参与信号传导 途径仍未知。在初步研究中，我们表明两种 UDP-GlcNAc 中的一种 (MurAA) 粪肠球菌中编码的 1-羧基乙烯基转移酶（催化肽聚糖的第一个关键步骤） 生物合成）是头孢菌素耐药性所特别需要的。 MurAA (MurAB) 的旁系同源物 不能驱动头孢菌素耐药性。因此，MurAA 拥有专门的、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 (i) IreK 通路和 MurAA 之间的生化联系尚未建立，并且 (ii) MurAA 驱动头孢菌素耐药的机制尚不清楚。这里提出的研究 旨在阐明 MurAA 在驱动生物过程中的作用的新见解 肠球菌头孢菌素耐药。通过这样做，我们将为基本原理提供新的见解。 驱动肠球菌关键抗生素耐药性的生物过程，并可能确定新的目标 旨在削弱肠球菌头孢菌素耐药性的创新疗法。