Prophylaxis of Clostridium difficile infection

 描述（由申请方提供）：艰难梭菌感染（CDI）是院内感染相关腹泻的主要可识别原因。仅在美国，每年约有50万例CDI病例，死亡率> 2.5%。每年与基础设施发展倡议有关的费用估计为32亿美元。C. difficile是孢子， 耐腐蚀结构，可以在医院表面上长时间生存。 C.艰难梭菌孢子不会引起疾病，但可以在住院患者的微生物耗尽的肠道中恢复为产毒素细菌（称为萌发的过程）。我们已经发现了一种合成的胆汁盐（CamSA），可以抑制C。艰难孢子萌发，更重要的是保护小鼠免受CDI而没有毒性作用。CamSA还与万古霉素协同作用以保护仓鼠免受CDI。虽然CamSA具有许多吸引人的特性，但仍需要针对临床前试验进行优化。我们组建了一个具有互补专业知识的团队，以帮助改善CamSA的药理学特性。在本项目开始时，我们将使用CamSA作为先导化合物完成必要的分析优化。CamSA获得的数据将作为新类似物（具体目标1）的基准，以进行体外和体内测试（具体目标2-4）。在每一步，GO/NO GO标准将消除次优的类似物。所收集的信息将用于合理设计和合成更有效和更稳定的抗萌发剂。该迭代过程将继续进行，直至获得优化的CDI预防性电极导线。具体目标是相互依存的。CamSA已经经历了这一过程的大部分，因为它很容易合成（具体目标1），在一系列体外试验中进行了测试（具体目标2），并在啮齿动物中作为CDI预防剂进行了测试（具体目标3）。此外，我们已经找到了三种新的抗发芽剂，可以进行体外和体内测试。

 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.