Intra-species regulatory functions of fsr

fsr的种内调节功能

• 批准号: 6826025
• 负责人: SATISH K PILLAI
• 金额: $ 4.92万
• 依托单位: BETH ISRAEL DEACONESS MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2004
• 资助国家: 美国
• 起止时间: 2004-07-01 至 2004-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6826025
• 关键词: Enterococcus; aminoglycoside antibiotics; bacterial genetics; bacterial proteins; beta lactam antibiotic; bioassay; biofilm; biological signal transduction; biotechnology; cell autolysis; drug screening /evaluation; genetic regulation; microorganism interaction; microorganism metabolism; mutagens; northern blottings; nucleic acid sequence; plasmids; quorum sensing; transcription factor; transposon /insertion element; vancomycin; virulence

DESCRIPTION (provided by applicant): Enterococcus faecalis is a leading cause of endocarditis, nosocomial bacteremia and urinary tract infections. Two characteristics contributing to the difficulty in treating enterococcal infections are (1) tolerance to beta- lactam antibiotics and (2) the propensity to cause biofilm-associated infections. The regulation of beta-lactam tolerance and biofilm formation remains incompletely defined. The applicant for this Research Career Award, Dr. Satish K. Pillai, proposes that the E. faecalis quorum-sensing locus fsr, based on its homology to the Staphylococcus aureus regulator agr, also functions as a global regulator. Using the agr paradigm, fsr represents a likely candidate by which E. faecalis regulates pathogenesis-enhancing characteristics like antibiotic tolerance and biofilm formation. Through proposed studies on isogenic fsr-positive and fsr-negative E. faecalis isolates, the applicant will (1) investigate fsr -mediated transcriptional control of biofilm associated genes and evaluate how environmental cues, such as glucose concentration, are relayed through fsr to modulate biofilm formation; (2) characterize fsr regulation of autolysis-dependent and autolysis-independent mechanisms of beta-lactam induced killing; and (3) simulate the conditions of chronic enterococcal infections by developing biofilms in the modified Robbins Device, in order to determine how fsr influences the overall response of E. faecalis to beta-lactam antibiotics, vancomycin, and aminoglycosides. The applicant is an Infectious Diseases fellow at Beth Israel Deaconess Medical Center, and will conduct this research under the mentorship of his sponsors, Drs. Robert C. Moellering, Jr., Roger T. Inouye and Peter F. Weller. In addition to his mentored research, the applicant's career development will by supplemented by course work in microbiology and genetics at Harvard Medical School, bacterial genetics training at Cold Springs Harbor Laboratory, and biostatistics courses at the Harvard School of Public Health. The goals of this application are to (1) define the regulation of enterococcal biofilm formation and beta-lactam tolerance in order to guide strategies to counter this increasingly prevalent pathogen and (2) allow the applicant to develop the skills needed to be an independent investigator.

描述（由申请人提供）：粪肠球菌是心内膜炎、医院菌血症和尿路感染的主要原因。导致治疗肠球菌感染困难的两个特征是（1）对β-内酰胺抗生素的耐受性和（2）引起生物膜相关感染的倾向。 β-内酰胺耐受性和生物膜形成的调节仍未完全确定。该研究职业奖的申请人 Satish K. Pillai 博士提出，基于与金黄色葡萄球菌调节因子 agr 的同源性，粪肠球菌群体感应位点 fsr 也具有全局调节因子的功能。使用 agr 范式，fsr 代表了粪肠球菌调节抗生素耐受性和生物膜形成等致病机制增强特征的可能候选者。通过对同基因 fsr 阳性和 fsr 阴性粪肠球菌分离株提出的研究，申请人将 (1) 研究 fsr 介导的生物膜相关基因的转录控制，并评估环境线索（例如葡萄糖浓度）如何通过 fsr 传递以调节生物膜形成； (2) 表征 β-内酰胺诱导杀伤的自溶依赖性和自溶非自溶机制的 FSR 调节； (3) 通过在改良的罗宾斯装置中形成生物膜来模拟慢性肠球菌感染的情况，以确定 fsr 如何影响粪肠球菌对 β-内酰胺抗生素、万古霉素和氨基糖苷类的总体反应。申请人是贝斯以色列女执事医疗中心的传染病研究员，并将在其赞助商 Drs. 的指导下进行这项研究。小罗伯特·C·莫勒林 (Robert C. Moellering, Jr.)、罗杰·T·井上 (Roger T. Inouye) 和彼得·F·韦勒 (Peter F. Weller)。除了他指导的研究之外，申请人的职业发展还将得到哈佛医学院微生物学和遗传学课程、冷泉港实验室细菌遗传学培训以及哈佛公共卫生学院生物统计学课程的补充。本申请的目标是 (1) 定义肠球菌生物膜形成和 β-内酰胺耐受性的调节，以指导对抗这种日益流行的病原体的策略，以及 (2) 允许申请人培养成为独立研究者所需的技能。