Prophylaxis of Clostridium difficile infection

艰难梭菌感染的预防

基本信息

批准号：
8818098
负责人：
Ernesto V Abel-Santos
金额：
$ 69.22万
依托单位：
UNIVERSITY OF NEVADA LAS VEGAS
依托单位国家：
美国
项目类别：
财政年份：
2014
资助国家：
美国
起止时间：
2014-12-01 至 2019-11-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8818098
关键词：
Acids Acquired Immunodeficiency Syndrome Amides Animal Model Antibiotics Bacteria Benchmarking Biological Assay Cells Cholic Acids Clostridium difficile Communicable Diseases Contracts Data Diarrhea Disease Drug Kinetics Environment Excretory function Fluoroquinolones Germination Goals Grant Hamsters Hospitals Human In Vitro Infection Infection prevention Inhibitory Concentration 50 Intestines Lead Leadership Link Malignant Neoplasms Mammalian Cell Maps Metabolism Metronidazole Modeling Modification Mus Patients Permeability Pharmaceutical Chemistry Prevention Process Property Prophylactic treatment Pump Relapse Reproduction spores Research Design Resistance Risk Rodent Serological Side Structure Structure-Activity Relationship Surface Symptoms Testing Toxic effect Toxicity Tests Toxin Transplant Recipients Treatment Failure Vancomycin absorption analog base bile salts cost design disorder control drug development genotoxicity gut microbiota improved in vitro Assay in vitro testing in vivo information gathering mortality mouse model pharmacophore pre-clinical preclinical study prevent prophylactic public health relevance

项目摘要

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.

描述（由申请人提供）：艰难梭菌感染 (CDI) 是院内抗生素相关性腹泻的一个主要病因，仅在美国，每年就有大约 500,000 例 CDI 病例，死亡率 >2.5%。相关成本估计为 32 亿美元。艰难梭菌的传染性形式是孢子，一种孢子。我们发现了一种合成的艰难梭菌孢子，可以在医院表面长时间存活，不会引起疾病，但可以在住院患者微生物群耗尽的肠道中恢复产生毒素的细菌（这一过程称为发芽）。胆汁盐 (CamSA) 可以抑制艰难梭菌孢子萌发，更重要的是可以保护小鼠免受 CDI 感染，而且不会产生毒性作用。 CamSA 还可以与万古霉素协同作用，保护仓鼠免受 CDI 感染。尽管 CamSA 有许多吸引人的特性，但它仍然需要针对临床前试验进行优化。我们已经组建了一支具有互补专业知识的团队来帮助改善 CamSA 的药理特性。在该项目开始时，我们将完成优化。使用 CamSA 作为我们的先导化合物进行必要的测定。为 CamSA 获得的数据将作为新类似物（具体目标 1）在体外和体内（具体目标 2-4）进行测试的基准。标准将消除收集到的信息将用于指导更有效和更稳定的抗芽剂的合理设计和合成，直到获得优化的 CDI 预防药物。具体目标被设计为相互依赖的。 CamSA 已经完成了这一过程的大部分，因为它很容易合成（具体目标 1），在一系列体外测定中进行测试（具体目标 2），并在啮齿动物中作为 CDI 预防剂进行测试（具体目标3) 此外，我们还发现了三种可用于体外和体内测试的新抗微生物剂，“启动了泵”。