Biogenesis and Function of Streptococcus Pyogenes Cell Wall

化脓性链球菌细胞壁的生物发生和功能

基本信息

批准号：
10292454
负责人：
Natalia Korotkova
金额：
$ 38.03万
依托单位：
UNIVERSITY OF KENTUCKY
依托单位国家：
美国
项目类别：
财政年份：
2019
资助国家：
美国
起止时间：
2019-11-25 至 2024-10-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10292454
关键词：
Acetylation Anabolism Analytical Chemistry Antibiotic Therapy Antibiotics Antimicrobial Cationic Peptides Antimicrobial Resistance Bacterial Physiology Binding Biochemical Biogenesis Biological Biological Assay Carbohydrates Cations Cell Wall Cell membrane Cell physiology Cells Cellulitis Charge Chemicals Communicable Diseases Control Groups Data Deacetylase Dental Development Diagnostic Disease Drug Design Drug Targeting Electrostatics Enzymatic Biochemistry Enzymes Epitopes Erysipelas Freeze Substitution Gene Cluster Genetic Glycerol Goals Histones Homologous Gene Human Infection Knowledge Link Mass Spectrum Analysis Methods Modeling Modification Molecular Molecular Genetics Molecular Structure Muramidase Necrotizing fasciitis Outcome Outcome Study Outcomes Research Pathogenesis Pathway interactions Peptidoglycan Permeability Pharyngeal structure Phospholipase A2 Polymers Polysaccharides Predisposition Proteins Publishing Rhamnose Role Scarlet Fever Serotyping Serum Side Skin Streptococcal Infections Streptococcal Vaccines Streptococcus Streptococcus mutans Streptococcus pyogenes Structure Surface Syndrome Techniques Testing Therapeutic Intervention Thick Vaccine Antigen Vaccine Design Vaccines Vertebral column Work analog antimicrobial antimicrobial peptide carbohydrate biosynthesis cell envelope combat density design drug development extracellular human pathogen improved in vivo in vivo Model inorganic phosphate insight molecular size mortality mouse model mutant neglect neutrophil novel pathogen pathogenic bacteria resistance mechanism targeted treatment vaccine candidate

项目摘要

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.

A 组链球菌（GAS，化脓性链球菌）是一种主要的细菌病原体。人的咽部和皮肤。近年来，严重侵袭性 GAS 明显复苏全世界都观察到了感染。 GAS 感染病例超过 65 万例每年发生严重侵袭性疾病。侵袭性 GAS 感染、坏死性筋膜炎、蜂窝织炎以及伴有猩红热和链球菌中毒综合征的丹毒，很难治愈用抗生素治疗，并且迫切需要 GAS 疫苗来对抗这种被忽视的疾病。一个 GAS 细胞壁的主要成分是 A 族碳水化合物 (GAC)，共价连接肽聚糖，由多鼠李糖主链和 N-乙酰葡糖胺 (GlcNAc) 组成侧链。 GAC 是一种有吸引力的候选疫苗，因为它在所有 GAS 中都有保守的表达血清型及其组成成分鼠李糖在人类中的缺失。我们的基因，生化和结构研究确定了 GAC 聚糖的两种新修饰：甘油 GAC 的磷酸盐修饰和 GAC 连接单元的脱 N-乙酰化。此举的目标提案旨在描述 GAC 生物合成和修饰的机制，以及阐明细胞壁修饰在抗菌素耐药机制和 GAS 中的作用发病。为了帮助回答这些问题，我们将采用各种遗传、生化、分析和结构方法。 GAS 细胞壁修饰的功能将在 GAS 感染的离体和体内模型中研究发病机制。拟议的研究为设计针对这一重要疾病的安全有效的疫苗提供了平台人类病原体，并且应该广泛应用于表达相似的其他链球菌细胞壁多糖。由于GAC生物合成途径的酶很有吸引力药物靶点，拟议的研究将对药物设计产生重要影响。