Inhibitor of FtsZ Polymerization in M. tuberculosis

结核分枝杆菌中 FtsZ 聚合的抑制剂

• 批准号: 6627839
• 负责人: Robert C Reynolds
• 金额: $ 55.12万
• 依托单位: SOUTHERN RESEARCH INSTITUTE
• 依托单位国家: 美国
• 财政年份: 2002
• 资助国家: 美国
• 起止时间: 2002-06-15 至 2005-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6627839
• 关键词: Mycobacterium tuberculosis; aminopyridines; antitubercular agents; bioassay; biological models; chemical kinetics; chemical structure function; chemical synthesis; cytotoxicity; diazepine; drug design /synthesis /production; drug screening /evaluation; electron microscopy; genetic strain; guanosinetriphosphatases; hydrolysis; laboratory mouse; macrophage; model design /development; polymerization; pteridines; tubulin

DESCRIPTION (Provided by the applicant): Development of new antitubercular agents is of critical importance worldwide. Our program has identified a new class of inhibitor of Mycobacterium tuberculosis(Mtb) that inhibits a novel protein not presently targeted by current antitubercular agents. The 2-alkoxy-carbonylamino-pyridines (2-ACPs) potently inhibit the growth of Mtb with an MIC99 (SRI-3072) as low as 0.15 microgram/ml (0.28 micromolar). Furthermore, SRI-3072 shows bactericidal activity, and shows significant activity in a murine-derived macrophage model with an EC90 & EC99 of 0.12 and 1.42 microgram/ml respectively. These analogs also show selective activity against Mtb versus a mammalian cell line. This program has successfully identified the target of these agents, the mycobacterial tubulin homolog FtsZ. The target protein has been cloned, expressed and isolated in quantities sufficient for development of in vitro polymerization and GTP hydrolysis assays. Three compounds, SRI-3072, SRI-76 14, and colchicine have been shown to inhibit polymerization of Mtb FtsZ in a dose dependent manner with IC50S of 50 uM, 60 uM, and 100 uM respectively. Furthermore. we have shown that SRI-7614 affects Mtb FtsZ polymerization by electron microscopy. SRI-7614 has also been shown to be active vs. a panel of single drug-resistant Mtb strains. We currently have crystal structures of Mtb FtsZ bound to citrate, GTPgS, and GDP. To date, about 200 2-ACP analogs have been screened in vitro against Mtb H37Rv. We have developed a SAR profile that will allow the preparation of more selective and more potent antitubercular agents. In this application, we propose to continue development of the 2-ACP class through preparations of new analogs of the more potent and selective subclasses, the 3-deaza-pteridines (priority), and the pyridodiazepines (backup). We will carefully evaluate these compounds for activity and selectivity in various in vitro assays including an in vitro Mtb H37Ra assay, an in vitro Mtb FtsZ polymerization and GTPase assay, an in vitro tubulin polymerization assay and a mammalian cell toxicity assay. Selected active agents will be further screened in an h in vitro macrophage model and a Mtb mouse model. The effect of inhibitors on FtsZ polymerization will be analyzed using electron microscopy. Data from the biological screening and the EM structural studies will feed back into compound design in an interactive, iterative drug design cycle that critically focuses on antibacterial potency and selectivity.

描述（由申请人提供）：新型抗结核药物的开发