Prophylaxis of Clostridium difficile infection

 描述(由申请人提供)：艰难梭菌感染(CDI)是医院内抗生素相关性腹泻的主要可识别原因。仅在美国，每年就有大约50万例CDI病例，死亡率为2.5%。每年与CDI相关的成本估计为32亿美元。艰难梭菌的感染形式是孢子，一种 能够在医院表面长时间存活的耐用结构。艰难梭菌孢子不会导致疾病，但可以在住院患者微生物区系枯竭的肠道中恢复为产生毒素的细菌(这一过程称为萌发)。我们已经发现了一种合成胆盐(CamSA)，它可以抑制艰难梭菌的孢子萌发，更重要的是，它可以保护小鼠免受CDI的影响，而不会产生毒性作用。CamSA还与万古霉素协同作用，保护仓鼠免受CDI的影响。虽然CamSA有许多有吸引力的特性，但它仍然需要优化以进行临床前试验。我们已经组建了一个具有互补专业知识的团队，以帮助改善CamSA的药理特性。在这个项目开始时，我们将使用CamSA作为先导化合物来完成必要的分析优化。为CamSA获得的数据将作为新类似物(特定目标1)在体外和体内(特定目标2-4)测试的基准。在每一步，通过/不通过标准将消除次优模拟。收集到的信息将用于合理设计和合成更有效、更稳定的抗发芽药物。这一迭代过程将继续进行，直到获得最佳的CDI预防性引线。具体目标的设计是相互依存的。CamSA已经经历了这一过程的大部分过程，因为它很容易合成(特异性目标1)，在一系列体外测试中进行测试(特异性目标2)，并在啮齿类动物身上作为CDI预防药物进行测试(特异性目标3)。此外，我们已经找到了三种新的抗菌药物，准备进行体外和体内试验，从而为泵做好了准备。

 DESCRIPTION (provided by applicant): Clostridium difficile infection (CDI) is a major identifiable cause of nosocomial antibiotic-associated diarrhea. In the US alone, there are approximately 500,000 CDI cases annually, with a mortality rate >2.5%. The annual CDI-associated costs are estimated at $3.2 billion. The infectious form of C. difficile is the spore, a resistant structure that can survive on hospital surfaces for extended periods. C. difficile spore do not cause disease, but can revert to toxin-producing bacteria (a process called germination) in the microbiota-depleted gut of hospitalized patients. We have found a synthetic bile salt (CamSA) that inhibits C. difficile spore germination and more importantly protects mice from CDI without toxic effects. CamSA also synergizes with vancomycin to protect hamsters from CDI. Although CamSA has many attractive properties, it still needs to be optimized for pre-clinical trials. We have assembled a team with complementary expertise to help improve the pharmacological properties of CamSA. At the start of this project, we will finish optimizing the necessary assays using CamSA as our lead compound. The data acquired for CamSA will serve as benchmarks for new analogs (specific aim 1) to be tested in vitro and in vivo (specific aims 2-4). At each step, GO/NO GO criteria will eliminate sub-optimal analogs. The information gathered will be used to inform the rational design and synthesis of more potent and stable anti- germinants. This iterative process will be continued until an optimized CDI prophylactic lead is obtained. The specific aims are designed to be interdependent. CamSA has already moved through much of this process since it was easily synthesized (specific aim 1), tested in a battery of in vitro assays (specific aim 2), and tested as a CDI prophylactic in rodents (specific aim 3). Moreover, we have "primed the pump" by finding three new anti-germinants that are ready for in vitro and in vivo testing.