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50，000例肠球菌感染 2017年感染率约为10%。大多数感染是由 粪肠球菌（Enterococcus faecalis）和E.包括菌血症、泌尿道和手术部位 感染和心内膜炎E. faecalis和E.粪便显示高水平的天然和 获得性抗生素耐药性严重限制了治疗选择。的主要组分 链球菌细胞壁的抗原是肠球菌多糖抗原（EPA）。最近解决的 EPA的结构由用聚核糖醇磷酸修饰的聚鼠李糖主链组成， 含有磷壁酸。虽然EPA生物合成的假设机制已经被证明是 提出，研究需要测试它。这个应用程序的目标是破译关键的 EPA多聚鼠李糖和磷壁酸组装步骤。此外，我们还将研究 EPA与肠球菌自溶素的结合及其对宿主的抗性机制 肠上皮细胞表达的抗菌蛋白ReG III γ。我们将利用 遗传学、分析和生物化学方法的结合来回答这些问题。的 EPA生物合成途径的酶构成了开发新的 抗肠球菌感染的抗生素。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， 治疗耐药感染的替代方法。此外，拟议的研究将 增强我们对EPA在抗菌素耐药性和持久性中的功能的理解 肠道菌群中的肠球菌

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.