Daptomycin Resistance in Enterococcus faecium

描述（由申请人提供）：该提案提出了一项为期五年的研究职业发展计划，重点研究屎肠球菌对脂肽抗生素达托霉素的耐药性机制。E.屎肠菌被认为是“非ESKAPE”病原体之一，并且由于其多药耐药性，日益增加的流行率， 高的可归因成本和有限的对该生物体具有可靠活性的抗生素。达托霉素是一种脂肽类抗生素，由于其体外抗菌活性强，已成为治疗肠球菌感染的最后药物。然而，随着使用的增加，达托霉素耐药肠球菌的出现也在增加。对临床分离的一对大肠杆菌进行全基因组序列比较。faecium鉴定了命名为YycFG的双组分调节系统的组氨酸激酶中的突变，YycFG是参与对抗生素的细胞包膜应答的必需双组分调节系统。YycFG在肠球菌达托霉素耐药性发展中的作用尚未得到表征。目前的建议旨在揭示YycFG调节子在达托霉素耐药性发展中的作用，并设计新的药理学策略以优化达托霉素在大肠杆菌中的使用。在YycFG系统中具有改变的屎肠菌分离物。具体目标I：大肠杆菌中YycFG细胞包膜调节子的表征。屎肠球菌和特定目标II：评价药物策略，以治疗达托霉素耐药E。屎室这项工作的成功完成将为深入了解E.并可能提供新的靶点，可以在治疗上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 多重耐药细菌。此外，该项目将作为一个平台，以支持一个年轻的临床研究人员的过渡到独立的专业知识将结合联合收割机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.