High Throughput Screening for Non-antibiotic inhibitors of Clostridium difficile Pathophysiology

项目摘要/摘要 艰难梭菌是抗生素相关性腹泻的主要原因。自2003年以来，其发病率和严重程度 艰难梭菌感染(CDI)的发病率在美国和全球都有所上升。2011年，美国约有29,000人死亡 从50万起CDI案件中脱颖而出。2013年，疾控中心将艰难梭菌列为紧急威胁。这些趋势是 与出现流行毒株有关，特别是027疫情。不幸的是，20%或更多的患者 用抗生素甲硝唑或万古霉素治疗后，会出现复发，这进一步令人沮丧 CDI的管理特点，因为复发的CDI患者的预后往往很差。CDI部分复发 甲硝唑或万古霉素对肠道微生物群落的破坏。有必要 用于在不损害肠道微生物区系的情况下解除艰难梭菌武装的替代治疗。这是 旨在开发一种新的高通量筛选(HTS)平台，用于 发现特殊抑制艰难梭菌毒力的非抗生素化合物，即抑制细胞 产生导致组织损伤的毒素和导致复发的孢子。 初步数据显示，这些分子不会损害微生物区系，并减少CDI复发的发生。 在动物身上。本研究提出建立毒素合成抑制剂的HTS平台是可行的 到参与这项研究的机构的最先进的设施和资源，如德克萨斯A&M健康科学 贝勒医学院圣裘德儿童研究医院中心和支持研究中心 德克萨斯医疗中心。该团队为HTS部署了一个大型化合物集合，包括自动和半自动 筛选技术，以及临床上反映CDI的新的体外和体内微生物区系模型。这个 研究结果将是一个或多个适合于铅优化和药物的候选支架 发展。这些分子将有助于探索不明确的分子致病机制 这种生物体的生物学。公共卫生。这项研究的成功完成对医疗保健产生了以下影响 推进药物开发的候选分子，通过减少CDI的发病来拯救生命。

PROJECT SUMMARY/ABSTRACT Clostridium difficile is the main cause of antibiotic-associated diarrhea. Since 2003, the incidence and severity of C. difficile infection (CDI) has risen in the U.S. and globally. In the U.S. in 2011, there were ~29,000 deaths from ~500,000 CDI cases. In 2013 the CDC designated C. difficile as an Urgent Threat. These trends were related to the emergence of epidemic strains, in particular epidemic 027. Unfortunately, 20% or more of patients treated with the antibiotics metronidazole or vancomycin, undergoes a recurrence, which is a further frustrating feature of managing CDI, as the prognosis for patients with recurrent CDI is often poor. CDI recurrence partly results from damage of the intestinal microbiota community by metronidazole or vancomycin. There is a need for alternative treatments that are specific to disarming C. difficile without harming the gut microbiota. This is addressed in the proposed study, which seeks to develop a novel high-throughput screening (HTS) platform for discovering non-antibiotic compounds that specially inhibits C. difficile virulence, namely inhibiting cellular production of toxins that are responsible for tissue damage and spores that are responsible for recurrence. Preliminary data shows that such molecules do not harm the microbiota and reduce the onset of recurrent CDI in animals. The study proposes to establish a HTS platform for toxin synthesis inhibitors, which is feasible owing to state-of-the art facilities and resources at institutions involved in the study i.e. Texas A&M Health Science Center, St Jude Children’s Research Hospital, Baylor College of Medicine and supporting research cores in the Texas Medical Center. The team deploys a large compound collection for HTS, automated and semi-automated screening technologies, and novel in vitro and in vivo microbiota models that are clinically reflective of CDI. The studies outcome will be one or more candidate scaffolds that are suitable for lead optimization and drug development. These molecules will help to probe ill-defined molecular pathogenic mechanisms to understand the biology of this organism. Public health. The successful completion of this study impacts healthcare by advancing candidate molecules for drug development to save lives by reducing the onset of CDI.