Allosteric therapy of the Clostridium difficile toxins

描述(申请人提供)：艰难梭菌感染(CDI)是美国细菌性腹泻最多发的原因之一，每年估计有300万例。艰难梭菌以其超强毒力的形式新出现，也会导致严重和潜在的 致命的结肠炎。由于艰难梭菌对抗生素治疗的耐药性正在迅速产生，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，但这两种药物都不是完全有效的，复发率高得令人无法接受就是明证。两种大型肠毒素(TcdA和TcdB)是艰难梭菌相关疾病的已知原因。尽管抗毒素疫苗计划目前正在进行临床试验，但这种方法的有效性仍然高度不确定，因为患有严重CDI的患者通常是老年人和危重患者。最近有报道称，全身抗毒素免疫治疗在预防CDI患者疾病复发方面是有效的，但未能带来显著的临床益处或缩短住院时间。口服适应被动抗毒素免疫治疗目前是不可行的，也不经济。因此，迫切需要开发治疗CDI的新的口腔疗法。我们的目标是通过对毒素毒力机制进行高度创新的研究，并通过开发口服变构疗法的原型概念来中和结肠中的毒素活性，来解决这些关键问题。TIS的工作将作为一项多机构合作努力进行，涉及艰难梭菌毒素的基础和临床专业知识，并在产生新的抗毒素疗法方面。

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.