Biogenesis and Function of Streptococcus Pyogenes Cell Wall

A组链球菌（GAS，化脓性链球菌）是一种主要的细菌病原体， 人咽和皮肤。近年来，严重侵入性GAS的惊人复苏 在世界范围内都观察到了感染。GAS感染病例超过65万例 严重的侵袭性疾病。侵袭性GAS感染、坏死性筋膜炎、蜂窝织炎 丹毒伴猩红热和链球菌中毒综合征， 因此，迫切需要GAS疫苗来对抗这种被忽视的疾病。一 GAS细胞壁的主要成分是A族碳水化合物（GAC）， 肽聚糖，由多聚鼠李糖骨架和N-乙酰葡糖胺（GlcNAc）组成 侧链由于GAC在所有GAS中的保守表达，因此GAC是一种有吸引力的疫苗候选物 血清型和缺乏其组成成分，鼠李糖，在人类。我们的基因， 生物化学和结构研究确定了GAC聚糖的两种新修饰：甘油 GAC的磷酸修饰和GAC连接单元的脱N-乙酰化。这个目标 建议是表征GAC生物合成和修饰的机制， 阐明细胞壁修饰在抗菌素耐药机制和GAS中的作用 发病机制为了帮助回答这些问题，我们将采用各种遗传，生物化学， 分析和结构方法。细胞壁修饰在GAS中的作用 将在GAS感染的离体和体内模型中研究发病机制。拟议 研究提供了一个平台，设计一个安全有效的疫苗，针对这一重要的 并应广泛应用于表达类似 细胞壁多糖由于GAC生物合成途径的酶是有吸引力的 药物靶点，拟议的研究将对药物设计产生重要影响。

Group A streptococcus (GAS, Streptococcus pyogenes) is a leading bacterial pathogen of the human pharynx and skin. In recent years, a striking resurgence in severe invasive GAS infections has been observed worldwide. GAS infections account for more than 650,000 cases of severe invasive disease annually. The invasive GAS infections, necrotizing fasciitis, cellulitis and erysipelas with concomitant scarlet fever and streptococcal toxic syndrome, are difficult to treat with antibiotics, and a GAS vaccine is urgently needed to combat this neglected disease. A major component of the GAS cell wall is the Group A Carbohydrate (GAC) covalently linked to peptidoglycan, consisting of a polyrhamnose backbone with N-acetylglucosamine (GlcNAc) side-chains. GAC is an attractive vaccine candidate due to its conserved expression in all GAS serotypes and the absence of its constitutive component, rhamnose, in humans. Our genetic, biochemical and structural studies identified two novel modifications of GAC glycans: glycerol phosphate modification of GAC and de-N-acetylation of the GAC linkage unit. The goal of this proposal is to characterize the mechanisms of GAC biosynthesis and modification, and elucidate the roles of cell wall modifications in antimicrobial resistance mechanisms and GAS pathogenesis. To help answer these questions we will employ a variety of genetic, biochemical, analytical and structural approaches. The function of cell wall modifications in GAS pathogenesis will be studied in ex vivo and in vivo models of GAS infection. The proposed studies provide a platform for design of a safe and effective vaccine against this important human pathogen and should have broad application to other streptococci which express similar cell wall polysaccharides. Since the enzymes of the GAC biosynthesis pathway are attractive drug targets, the proposed studies will have important implications for drug design.