Bacterial RNase P as a Target for Novel Antimicrobials

细菌 RNase P 作为新型抗菌药物的靶标

基本信息

批准号：
6443668
负责人：
PAUL S EDER
金额：
$ 9.9万
依托单位：
MESSAGE PHARMACEUTICALS, INC.
依托单位国家：
美国
项目类别：
财政年份：
2002
资助国家：
美国
起止时间：
2002-03-15 至 2002-12-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/6443668
关键词：
Neisseria gonorrhoeae antibacterial agents antiinfective agents bacterial proteins biochemical evolution drug design /synthesis /production enzyme inhibitors human tissue ribonuclease P

项目摘要

DESCRIPTION (provided by applicant): Antibiotic resistance is a growing health threat worldwide. Small-molecule screens that target specific complexes that are essential for bacterial metabolism will be useful in identifying new classes of microbial inhibitors. Bacterial RNase P represents an excellent target for developing novel anti-infectives: it is essential for viability of bacteria; it is well-characterized enzymatically and structurally; and it differs structurally and functionally from mammalian RNase P. Message Pharmaceuticals is dedicated to developing drugs that target RNA via post-transcriptional regulation. With its high-throughput capacity, Message has screened nearly 150,000 compounds for inhibitors of Neisseria gonorrhoeae RNase P. More than fifty compounds among six classes have exhibited dose-dependent inhibition of N. gonorrhoeae RNase P in vitro. Message proposes to develop these classes of leads further by: 1) determining their minimal inhibitory concentration endpoint against known bacterial isolates; 2) measuring the inhibition of RNase P enzymes from other evolutionarily diverse pathogenic bacteria; 3) comparing the inhibition to that of human RNase P; 4) assessing cytotoxicity in mammalian cells in culture. In addition to identifying novel anti-infectives, the results will advance our understanding of the function of an evolutionarily ancient RNA enzyme, and, more importantly, reveal new classes of small molecules that interact with structured RNAs. PROPOSED COMMERCIAL APPLICATION: With the worldwide emergence and expansion of antibiotic resistance in both the nosocomial and community settings, new classes of antibiotics are needed to combat the resistance. The results from this grant will contribute to the development of novel classes of antibiotics for a variety of resistant bacterial infections.

描述（由申请人提供）：抗生素耐药性是一种日益严重的健康状况全球威胁。针对特定复合物的小分子屏幕对于细菌代谢至关重要微生物抑制剂类别。细菌RNase P代表了极好的开发新型抗感染的目标：这对于生存能力至关重要细菌;它在酶上和结构上都是良好的酶。然后结构和功能与哺乳动物RNase P不同。消息。药物专门用于开发靶向RNA的药物转录后调节。凭借其高通量能力，信息具有筛选了近150,000种化合物，用于淋病尿菌的抑制剂 P.六类中有五十多种化合物表现出剂量依赖性在体外抑制淋病链球菌RNase P。消息建议开发这些铅的类别进一步：1）确定其最小的抑制针对已知细菌分离株的浓度终点； 2）测量抑制来自其他进化多种致病性的RNase P酶细菌; 3）将抑制与人RNase P进行比较； 4）评估培养哺乳动物细胞中的细胞毒性。除了识别小说反感染者，结果将提高我们对一种进化上古老的RNA酶，更重要的是揭示了新的类别与结构化RNA相互作用的小分子。拟议的商业应用：随着全球出现和抗生素耐药性在医院和社区环境中的扩展，需要新的抗生素来对抗抵抗。该赠款的结果将有助于开发各种抗性细菌感染的新型抗生素类。