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Mechanisms of Clostridium difficile spore germination

艰难梭菌孢子萌发机制

基本信息

批准号：
9248867
负责人：
Joe Sorg
金额：
$ 35.75万
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/9248867
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 Diarrhea Disease Environment Enzymes Excretory function Exposure to Gallbladder Gastrointestinal tract structure Genetic Screening Germination Glycine Goals Growth Healthcare Healthcare Systems 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 Surface Symptoms Taurine Taurocholic Acid Testing Titrations Toxin Translating United States Water Work analog base combat cost design experimental study hydroxyl group in vivo inhibitor/antagonist mortality mutant novel novel therapeutics public health relevance receptor

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).