Functional Role of the Enterococcal Polysaccharide Antigen

肠球菌是住院患者感染的主要原因之一， 长期护理设施的居民。在美国，有超过5万例肠球菌感染病例 2017年感染，病死率约10%。大多数感染是由 粪肠球菌和粪肠球菌，包括菌血症、尿路和手术部位 感染和心内膜炎。粪肠球菌和粪肠球菌表现出高水平的天然和 获得性抗生素耐药性严重限制了治疗选择。的主要组成部分 链球菌细胞壁是肠球菌多糖抗原(EPA)。最近解决的 EPA的结构是由多聚鼠李糖主链装饰的聚核糖醇磷酸- 含有磷壁酸。虽然EPA生物合成的假想机制是 提出，需要进行研究来测试它。这个应用程序的目标是解密关键的 EPA多鼠李糖和磷壁酸组装的步骤。此外，我们还将研究 EPA与肠球菌自溶素结合及其对宿主的耐药机制 在肠上皮细胞中表达的抗菌蛋白ReGIIIγ。我们将利用一个 结合遗传、分析和生化方法来回答这些问题。这个 EPA生物合成途径中的酶是开发新型药物的良好靶点 对抗肠球菌感染的抗菌药。因此，拟议的实验将提供一个 更好地了解肠球菌的细胞壁生物发生，使其能够发展为 治疗耐药感染的替代方法。此外，拟议的研究将 提高对EPA在抗菌药耐药性和持久性中的作用的认识 肠道微生物区系中的肠球菌。

Enterococci represent one of the leading causes of infections among hospitalized patients and residents of long-term care facilities. In the USA, there were over 50,000 cases of enterococcal infections in 2017, with ~10% fatality rate. The majority of infections are caused by Enterococcus faecalis and E. faecium, which include bacteremia, urinary tract and surgical sites infections, and endocarditis. E. faecalis and E. faecium display high levels of natural and acquired antibiotic resistance that severely limits the treatment options. The major component of streptococcal cell wall is the Enterococcal Polysaccharide Antigen (EPA). The recently solved structure of EPA consists of a polyrhamnose backbone decorated with a polyribitol phosphate- containing teichoic acid. While a hypothetical mechanism of EPA biosynthesis has been proposed, studies are required to test it. The goal of this application is to decipher the critical steps of EPA polyrhamnose and teichoic acid assembly. In addition, we will examine the role of EPA in binding to the enterococcal autolysins and the resistance mechanism to host antimicrobial protein expressed in the intestinal epithelial cells, ReGIIIγ. We will utilize a combination of genetic, analytical and biochemical methods to answer these questions. The enzymes of EPA biosynthetic pathway constitute promising targets for the development of novel antimicrobials to combat enterococcal infections. Thus, the proposed experiments will provide a better understanding of cell wall biogenesis in enterococci to enable the development of alternative approaches to treat drug-resistant infections. Furthermore, the proposed studies will enhance our understanding of the functions of EPA in antimicrobial resistance and persistence of enterococci in gut microbiota.