Daptomycin Resistance in Enterococcus faecium

描述(申请人提供)：本提案提出了一个为期五年的研究生涯发展计划，重点研究粪肠球菌对脂肽类抗生素达托霉素的耐药机制。粪肠球菌是已知的“非ESKAPE”病原体之一，由于其多重耐药的性质，发病率不断上升，已成为临床上成功治疗最具挑战性的微生物之一。 高昂的可归因性成本和有限的抗生素，对这种微生物具有可靠的活性。达托霉素是一种脂肽类抗生素，具有较强的体外活性，已成为治疗肠球菌感染的最后药物。然而，随着使用量的增加，耐达托霉素肠球菌的出现呈上升趋势。先前对一对临床粪便埃希菌株的全基因组序列比较发现，一个名为YycFG的双组分调控系统的组氨酸激酶发生突变，这是一个重要的双组分调控系统，参与细胞对抗生素的反应。YycFG在肠球菌对达托霉素耐药中的作用尚不清楚。目前的建议旨在揭示YycFG调节子在达托霉素耐药性产生中的作用，并设计新的药理学策略来优化YycFG系统发生变化的粪肠球菌中达托霉素的使用。这项提案概述了以下具体目标：具体目标一：确定粪肠球菌YycFG细胞膜调节子的特征；具体目标二：评价治疗达托霉素耐药的粪肠球菌的药理策略。这项工作的成功完成将对粪肠球菌耐药性和细胞壁稳态的遗传动力学提供深入的见解，并可能提供新的靶点，可以通过治疗来探索，以克服达托霉素耐药性的上升，最终目标是帮助临床医生改善对感染的患者的治疗。 耐多药细菌。此外，该项目将作为一个平台，支持年轻的临床医生-研究人员向独立的过渡，他的专业知识将结合细菌分子遗传学和抗菌药理学。

DESCRIPTION (provided by applicant): This proposal presents a five-year research career development program focused on the study of the mechanism of resistance of Enterococcus faecium to the lipopeptide antibiotic daptomycin. E. faecium is known as one of the "no-ESKAPE" pathogens and has become one of the most challenging organisms to treat successfully in the clinical setting due to its multi-drug resistant nature, increasing prevalence, high attributable costs and limited antibiotics with reliable activity against this organism. Daptomycin is a lipopeptide antibiotic which has become the last-resort drug for the treatment of enterococcal infections due to is potent in vitro activity. However, with increasing use, the emergence of daptomycin-resistant Enterococcus is on the rise. Previous whole genome sequence comparison of a clinical strain-pair of E. faecium identified mutation in the histidine kinase of a two-component regulatory system designated YycFG, which is an essential two-component regulatory system involved in the cell envelope response to antibiotics. The role of YycFG in the development of daptomycin resistance in enterococci has not been characterized. The current proposal aims to uncover the role of the YycFG regulon in development of daptomycin resistance and design new pharmacological strategies to optimize the use of daptomycin in E. faecium isolates with alterations in the YycFG system. The following specific aims are outlined in this proposal: Specific Aim I: Characterization of the YycFG cell envelope regulon in E. faecium and Specific Aim II: Evaluation of pharmacologic strategies to treat daptomycin-resistant E. faecium. Successful completion of this work will provide insights into the genetic dynamics of resistance and cell-wall homeostasis of E. faecium and is likely to provide novel targets that could be explored therapeutically to overcome the rise of daptomycin resistance with the ultimate goal of helping clinicians improve treatment of patients infected with multidrug-resistant bacteria. Additionally, this project will serve as a platform to support the transition of a young clinician-researcher to independence whose expertise will combine bacterial molecular genetics and antimicrobial pharmacology.