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: 10215113
• 负责人: CHRISTOPHER J KRISTICH
• 金额: $ 19.5万
• 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 2023-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10215113
• 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/antagonist; 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