Mechanisms of Clostridium difficile spore germination

艰难梭菌孢子萌发机制

基本信息

批准号：
8862916
负责人：
Joe Sorg
金额：
$ 27.02万
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/8862916
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 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 public health relevance 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（由申请人提供）：艰难梭菌是医院和长期医疗机构中抗生素相关性腹泻的主要原因。除了患者死亡之外，艰难梭菌感染还给美国医疗保健带来与治疗相关的费用。尽管美国的艰难梭菌感染率正在上升，但令人惊讶的是，人们对艰难梭菌的发病机制知之甚少。为了引起疾病，孢子必须在胃肠道中对触发萌发的信号作出反应，从而在排泄到环境中之前作为营养细菌生长、产生毒素并随后形成孢子。研究表明，牛磺胆酸（一种通常存在于胃肠道中的胆汁酸）和甘氨酸是艰难梭菌孢子的共同发芽剂。鹅去氧胆酸可抑制牛磺胆酸介导的萌发，并且对艰难梭菌营养生长有毒。我们最近确定了艰难梭菌孢子上胆汁酸的分子靶标，从而确定了第一个艰难梭菌孢子萌发受体。长期目标是了解艰难梭菌萌发的分子机制，并利用这些知识合理设计艰难梭菌感染的抑制剂。提议：（1）确定艰难梭菌孢子萌发受体如何与胆汁酸相互作用；（2）确定艰难梭菌孢子中萌发受体的结合伙伴和超微结构位置；（3）确定谁 CspC 传输胆汁；酸信号启动孢子萌发；（4）鉴定其他艰难梭菌萌发受体。成功完成本文概述的实验将扩展我们对艰难梭菌机制的理解。艰难梭菌萌发，为艰难梭菌孢子形成和孢子萌发的研究开辟了新途径，并导致鉴定其他孢子形成细菌中新发现的萌发受体的同源物（开辟其他研究途径）。