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

• 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
• 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

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)是引起肺炎的主要致病菌。 人类的咽部和皮肤。近年来，严重侵入性气体的显著复苏 在世界各地都观察到了感染。气体感染占65万多例 严重的侵袭性疾病。侵袭性气体感染、坏死性筋膜炎、蜂窝织炎 和丹毒伴随的猩红热和链球菌中毒综合征，很难 用抗生素治疗，迫切需要一种气体疫苗来对抗这种被忽视的疾病。一个 气体细胞壁的主要成分是A族碳水化合物(GAC)共价连接到 肽聚糖，由多鼠李糖骨架和N-乙酰氨基葡萄糖(GlcNAc)组成 侧链。GAC是一个有吸引力的候选疫苗，因为它在所有的气体中都有保守的表达 人类的血清型及其组成成分鼠李糖的缺失。我们的基因， 生化和结构研究证实了GAC葡聚糖的两种新的修饰：甘油 GAC的磷酸化修饰和GAC连接单元的脱乙酰化。这样做的目的是 建议对GAC生物合成和修饰的机制进行表征，以及 阐明细胞壁修饰在抗菌素耐药机制和GAS中的作用 发病机制。为了帮助回答这些问题，我们将利用各种遗传、生化、 分析方法和结构方法。细胞壁修饰在GAS中的作用 致病机制将在体外和体内GAS感染模型中进行研究。建议数 研究为设计安全有效的预防这种重要疾病的疫苗提供了平台 人类致病菌，应广泛应用于其他表达类似的链球菌 细胞壁多糖。由于GAC生物合成途径的酶很有吸引力 在药物靶点方面，拟议的研究将对药物设计产生重要影响。