Mechanisms of Clostridium difficile spore germination

艰难梭菌孢子萌发机制

基本信息

批准号：
9040882
负责人：
Joe Sorg
金额：
$ 35.82万
依托单位：
TEXAS A&M UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2015
资助国家：
美国
起止时间：
2015-04-01 至 2020-03-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9040882
关键词：
Air Amino Acids Anaerobic Bacteria Antibiotic Resistance Antibiotics Appearance Bacteria Bile Acids Binding Binding Proteins Calorimetry Cells Chenodeoxycholic Acid Cholesterol Cholic Acids Clostridium difficile Computer Simulation Deposition Diarrhea Disease Environment Enzymes Excretory function Exposure to Gallbladder Gastrointestinal tract structure Genetic Screening Germination Glycine Goals Growth Health Healthcare Healthcare Systems Homologous Gene Hospitals Human Immunocompromised Host In Vitro Infection Investigation Knowledge Lead Liver Location Mediating Membrane Molecular Molecular Target Morbidity - disease rate Osmolar Concentration Pathogenesis Pathway interactions Patient risk Patients Peptide Hydrolases Peptidoglycan Phase Production Proteins Publications Reaction Reporting Reproduction spores Role Scanning Signal Transduction Staging Surface Symptoms Taurine Taurocholic Acid Testing Titrations Toxin Translating United States Water Work analog base combat cost design hydroxyl group in vivo inhibitor/antagonist mortality mutant novel novel therapeutics receptor research study

项目摘要

DESCRIPTION (provided by applicant): Clostridium difficile is the leading cause of antibiotic-associated diarrhea in the hospital and long term health care settings. In addition to the patient toll, the treatment-associated costs of C. difficile infections to the United States healthcare system have been estimated at $3.2 billion. Although the rate of C. difficile infection in the United States is rising, surprisingly little is known about the mechanisms of C. difficile pathogenesis. C. difficile is believed to be acquired by the host in the form of a dormant spore. To cause disease, the spore must respond in the gastrointestinal tract to signals that trigger germination, thereby allowing growth as a vegetative bacterium, toxin production and subsequent spore formation before excretion into the environment. We have shown that taurocholic acid, a bile acid normally found in the GI tract, and glycine are co-germinants for C. difficile spores. Another bile acid, chenodeoxycholic acid, inhibits taurocholic acid-mediated germination and is toxic for C. difficile vegetative growth. We recently identified the molecular target of bile acids on the C. difficile spore thus identifying the first C. difficile spore germinnt receptor. Our long-term goal is to understand the molecular mechanisms of C. difficile germination and use that knowledge to rationally design inhibitors of C. difficile infection. In ths application, we propose to: (1) identify how the C. difficile spore germinant receptor interacts with bile acids; (2) identify binding partners and the ultrastructural location of the germinant receptor in the C. difficile spore; (3) determine who CspC transmits the bile acid signal to initiae spore germination; and (4) identify other C. difficile germinant receptors. Successful completion of the experiments outlined herein will extend our understanding of the mechanisms of C. difficile germination, open new avenues in the study of C. difficile spore formation and spore germination and lead to the identification of homologs of the newly discovered germinant receptors in other spore-forming bacteria (opening other avenues of investigation).

描述（由适用提供）：艰难梭菌是医院和长期医疗保健环境中与抗生素相关的腹泻的主要原因。除了患者损失外，艰难梭菌感染与治疗相关的成本估计为32亿美元。尽管美国艰难梭菌感染的速度正在上升，但令人惊讶的是，关于艰难梭菌发病机理的机制知之甚少。据信，艰难梭菌被宿主以休眠酱的形式获取。为了引起疾病，酱汁必须在胃肠道中对引发发芽的信号做出反应，从而使生长作为营养细菌，毒素的产生以及随后的散射形成，然后再排出环境。我们已经表明，牛胆酸是通常在胃肠道中发现的胆汁酸，甘氨酸是艰难梭菌孢子的共晶。另一种胆汁酸氯迪氧胆酸抑制了牛螺胆酸介导的发芽，对艰难梭菌营养生长有毒。我们最近鉴定出胆汁酸在艰难梭菌孢子上的分子靶标，从而鉴定出艰难梭菌孢子发明受体。我们的长期目标是了解艰难梭菌发芽的分子机制，并了解艰难梭菌感染的理性设计抑制剂。在应用中，我们建议：（1）确定艰难梭菌发芽受体如何与胆汁酸相互作用；（2）确定结合伴侣和发芽受体在艰难梭菌孢子中的超微结构位置；（3）确定谁CSPC将胆汁酸信号传输到Initiale酱发芽；（4）确定其他艰难梭菌发芽的受体。在本文中概述的实验的成功完成将扩展我们对艰难梭菌发芽的机制，开放的新途径，在研究艰难梭菌酱形成和摩擦发芽的研究中，并导致鉴定出新发现的新酱中新发现的受体的同源物（开放其他投资途径）。