Allosteric therapy of the Clostridium difficile toxins

艰难梭菌毒素的变构疗法

基本信息

批准号：
8463992
负责人：
Tor C. Savidge
金额：
$ 36.97万
依托单位：
BAYLOR COLLEGE OF MEDICINE
依托单位国家：
美国
项目类别：
财政年份：
2012
资助国家：
美国
起止时间：
2012-06-01 至 2017-05-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8463992
关键词：
Active Sites Address Allosteric Site Alternative Therapies Animal Model Antibody Formation Antimicrobial Resistance Antitoxins Binding Biological Assay Biological Availability Catabolism Cell membrane Cells Cleaved cell Clinical Clinical Trials Clostridium difficile Colon Computer Simulation Critical Illness Cysteine Cysteine Protease Cytosol Development Diarrhea Diet Disease Drug Formulations Drug resistance Elderly Enterotoxins Epidemic Exotoxins Feces Fluids and Secretions Goals Hospitalization Hospitals Host Defense Mechanism Human Immune response Immunotherapy In Vitro Incidence Infection Inflammation Inflammatory disease of the intestine Inositol Phosphates Intestinal Diseases Intestines Lead Length Libraries Methods Metronidazole Microbe Modeling Molecular Target Mucositis Oncogene Proteins Oral Outcome Patients Physiological Phytic Acid Process Protease Domain Public Health Recurrent disease Relapse Reliance Reporting Resistance development S-Nitrosoglutathione Signal Transduction Specificity Sulfhydryl Compounds Symptoms Targeted Toxins Testing Therapeutic Toxin United States Vaccines Vancomycin Virulence Work Xenograft procedure analog base chemical synthesis cofactor cost design in vitro Model in vitro activity in vivo inhibitor/antagonist innovation microbial novel novel therapeutics pathogen pre-clinical premature prevent programs small molecule

项目摘要

DESCRIPTION (provided by applicant): Clostridium difficile infection (CDI) is one of the most prolific causes of bacterial-induced diarrhea in the United States, with 3 million cases estimated annually. Newly emerged in its hypervirulent form, C. difficile also causes serious and potentially fatal inflammation of the colon. Because C. difficile is rapidly developing resistance to antibioti treatment, there is an urgent need to find an alternative therapy. Vancomycin and metronidazole remain treatment options for CDI, but neither is fully effective as is evident by the unacceptably high relapse rates. Two large enterotoxins (TcdA and TcdB) are the known causes of C. difficile-associated disease. Although an antitoxin vaccine program is currently in clinical trials, the efficacy of this approach remains highly uncertain since patients with severe CDI typically tend to be the elderly and the critically ill. Systemic antitoxin immunotherapy has recently been reported to be effective in preventing disease relapse in CDI patients, but fails to confer significant clinical benefits or reduce the length of hospitalization. Oral adaptation of passive antitoxin immunotherapy is currently not feasible or economical. Thus, there is an urgent need to develop new oral therapeutics for CDI. Our goal is to address these critical issues by performing highly innovative studies of the toxin virulence mechanism and by developing prototypic concepts for oral allosteric therapeutics that neutralize toxin activity in the colon. Tis work will be performed as a multi-institutional collaborative effort involving basic and clinical expertise of the C. difficile toxins, and in generating novel antitoxin therapeutics.

描述（由申请人提供）：艰难梭菌感染（CDI）是美国细菌引起的腹泻最多产的原因之一，每年估计300万例病例。艰难梭菌新出现以其过度呼吸的形式，也会引起严重的结肠致命炎症。由于艰难梭菌正在迅速发展对抗生素治疗的耐药性，因此迫切需要找到一种替代疗法。万古霉素和甲硝唑仍然是CDI的治疗选择，但由于不可接受的高复发速率可以看出，这两种方法都不完全有效。两种大型肠毒素（TCDA和TCDB）是艰难梭菌相关疾病的已知原因。尽管目前正在临床试验中进行抗毒素疫苗计划，但这种方法的疗效仍然高度不确定，因为严重CDI的患者通常往往是老年人和重症患者。据报道，全身性抗毒素免疫疗法可有效预防CDI患者的疾病复发，但未能赋予明显的临床益处或减少住院时间。被动抗毒素免疫疗法的口服适应目前不可行或不经济。因此，迫切需要为CDI开发新的口服治疗剂。我们的目标是通过对毒素毒力机制进行高度创新的研究，并为口服变构治疗剂进行原型概念来解决这些关键问题，以中和结肠中的毒素活性中和。 TIS的工作将作为涉及艰难梭菌毒素的基本和临床专业知识的多机构合作努力，并在产生新型的抗毒素疗法方面。