Functional Role of the Enterococcal Polysaccharide Antigen

肠球菌多糖抗原的功能作用

基本信息

批准号：
10625496
负责人：
Konstantin V Korotkov
金额：
$ 19.13万
依托单位：
UNIVERSITY OF KENTUCKY
依托单位国家：
美国
项目类别：
财政年份：
2022
资助国家：
美国
起止时间：
2022-05-20 至 2025-04-30
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10625496
关键词：
Acetylgalactosamine Adherence Anabolism Antibiotic Resistance Antibiotics Antigens Antimicrobial Resistance Autolysin Autolysis Automobile Driving Bacteremia Bacteriophages Binding Biochemical Biogenesis Biological Assay Biological Process Cell Wall Cell membrane Cells Cellular Morphology Complement Daptomycin Data Development Drug Controls Drug resistance Endocarditis Enterococcus Enterococcus faecalis Enterococcus faecium Enzymatic Biochemistry Enzymes Epithelial Cells Essential Genes Evolution Exhibits Fatality rate Future Genes Genetic Genome Glycobiology Goals Gram-Positive Bacteria Health care facility Hospitalization Hospitals Host Defense Human In Vitro Infection Intestines Ions Life Lipids Long-Term Care Mediating Methods Microbial Biofilms Microscopy Modeling Molecular Molecular Genetics Mucous body substance Multi-Drug Resistance Muramidase New Agents Outcome Pathway interactions Patients Peptidoglycan Permeability Phagocytes Phospholipase A2 Physiology Play Polysaccharides Proteins Resistance Role Site Streptococcus Structure Surface Surgical Wound Infection Teichoic Acids Testing Thick Urinary tract Vancomycin Resistance Vertebral column Virulence antimicrobial antimicrobial peptide beta-Lactams combat experimental study gut microbiota inorganic phosphate intestinal epithelium novel novel therapeutics pathogen polyribitol phosphate resistance mechanism therapeutic target trait

项目摘要

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.

肠球菌是住院患者和患者感染的主要原因之一在美国，长期护理机构的居民中有超过 50,000 例肠球菌病例。 2017 年感染人数约为 10%，大多数感染是由以下原因引起的。粪肠球菌和屎肠球菌，包括菌血症、尿路和手术部位感染和心内膜炎。粪肠球菌和屎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。链球菌细胞壁是最近解决的肠球菌多糖抗原（EPA）。 EPA 的结构由用聚核糖醇磷酸酯装饰的聚鼠李糖主链组成含有磷壁酸，而 EPA 生物合成的假设机制已被证实。提出后，需要进行研究来测试它，该应用程序的目标是破译关键点。 EPA多鼠李糖和磷壁酸组装的步骤此外，我们将研究其作用。 EPA与肠球菌自溶素的结合及其对宿主的耐药机制我们将利用肠上皮细胞中表达的抗菌蛋白 ReGIIIγ。结合遗传学、分析和生化方法来回答这些问题。 EPA生物合成途径的酶构成了开发新型药物的有希望的目标因此，拟议的实验将提供一种对抗肠球菌感染的抗菌药物。更好地了解肠球菌的细胞壁生物发生，以促进开发此外，拟议的研究将提供治疗耐药感染的替代方法。增强我们对 EPA 在抗菌药物耐药性和持久性方面的功能的理解肠道菌群中的肠球菌。