Allosteric therapy of the Clostridium difficile toxins

描述（由申请方提供）：艰难梭菌感染（CDI）是美国细菌性腹泻最常见的原因之一，估计每年有300万例病例。新出现的高毒力型，C。difficile也会导致严重的和潜在的 致命的结肠炎。因为C.艰难梭菌正在迅速发展对抗生素治疗的抗性，迫切需要找到替代疗法。万古霉素和甲硝唑仍然是CDI的治疗选择，但两者都不是完全有效的，因为不可接受的高复发率是显而易见的。两种大的肠毒素（TcdA和TcdB）是已知的C。艰难梭相关疾病虽然抗毒素疫苗项目目前正在进行临床试验，但这种方法的疗效仍然高度不确定，因为重度CDI患者通常是老年人和危重病患者。最近有报道称，全身性抗毒素免疫治疗可有效预防CDI患者的疾病复发，但未能带来显著的临床获益或缩短住院时间。被动抗毒素免疫疗法的口服适应目前是不可行的或经济的。因此，迫切需要开发用于CDI的新的口服疗法。我们的目标是通过对毒素毒力机制进行高度创新的研究，并通过开发中和结肠中毒素活性的口服变构疗法的原型概念来解决这些关键问题。这项工作将作为一个多机构的合作努力，涉及基础和临床专业知识的C。艰难梭菌毒素和产生新的抗毒素治疗剂。 公共卫生相关性：这项工作将使用机械方法合理设计和合成新型别构治疗艰难梭菌感染，导致广泛的肠道疾病。

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. PUBLIC HEALTH RELEVANCE: This work will use mechanistic approaches for the rational design and synthesis of novel allosteric therapeutics for Clostridium difficile infection, which causes widespread intestinal disease.