Allosteric therapy of the Clostridium difficile toxins

艰难梭菌毒素的变构疗法

• 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
• 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

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。新出现的高毒力形式的艰难梭菌也会导致严重且潜在的 致命的结肠炎症。由于艰难梭菌正在迅速产生对抗生素治疗的耐药性，因此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，但这两种药物都不是完全有效，其复发率高得令人无法接受，这证明了这一点。两种大的肠毒素（TcdA 和 TcdB）是艰难梭菌相关疾病的已知原因。尽管抗毒素疫苗项目目前正处于临床试验阶段，但这种方法的功效仍然高度不确定，因为严重 CDI 患者通常是老年人和危重患者。最近有报道称，全身抗毒素免疫疗法可有效预防 CDI 患者疾病复发，但未能带来显着的临床益处或缩短住院时间。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，迫切需要开发新的 CDI 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开发中和结肠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。这项工作将作为多机构合作进行，涉及艰难梭菌毒素的基础和临床专业知识，并产生新型抗毒素疗法。