Discovery of antitubercular PptT inhibitors

描述(由申请人提供)：该计划旨在确定与结核分枝杆菌(Mtb)产生霉酚酸相关的4‘-磷酸丙氨酸基转移酶(PPTase)PptT的抑制物。PptT负责激活霉菌酸合成酶，霉菌酸合成酶是参与分枝杆菌细胞壁生物合成的一种重要蛋白质，也是新验证的药物靶点。我们最近与NIH化学基因组中心(NCGC)合作，完成了一项高通量筛选(HTS)工作，以确定SFP的抑制剂枯草杆菌表面蛋白PPTase。在这里，我们试图探索在这个筛选中确定的抗PptT活性的HITS，并评估它们对野生型和耐药结核分枝杆菌菌株的抗菌活性。鉴于我们从SFP HTS努力中获得的初步结果，一种强大和通用的PPTase分析的开发，这种病原体对药物开发的重要性，以及最近PptT作为具有抗生素开发潜力的可药物靶点的验证，我们预计在该项目的时间框架内将发现一类新的抗微管化合物。 公共卫生相关性：结核分枝杆菌(结核分枝杆菌)是世界上死于一种细菌传染病的主要原因，每年影响18亿人。该计划研究了一种新的治疗方法的开发，该治疗方法针对与结核分枝杆菌(Mtb)产生霉菌酸相关的4‘-磷酸丙氨酸基转移酶(PPTase)PptT，目的是在资助期间确定一组先导化合物，

DESCRIPTION (provided by applicant): This program aims to identify inhibitors of the 4'-phosphopantetheinyltransferase (PPTase) PptT associated with mycolic acid production in Mycobacterium tuberculosis (Mtb). PptT is responsible for activation of mycolic acid synthase, an essential protein involved in the biosynthesis of the mycobacterial cell wall and a newly validated drug target. We have recently completed a high-throughput screening (HTS) effort to identify inhibitors against Sfp, the Bacillus subtilis surfactin PPTase, in collaboration with the NIH Chemical Genomics Center (NCGC). Here we seek to probe the hits identified in this screen for activity against PptT and evaluate their antibacterial activity against wild type and drug resistant Mtb strains. Given our preliminary results from the Sfp HTS effort, the development of a robust and general PPTase assay, the importance of this pathogen for drug development, and the recent validation of PptT as a druggable target with potential for antibiotic development, we anticipate discovery of a new class of antitubucular compounds within the timeframe of this project. PUBLIC HEALTH RELEVANCE: Mycobacterium tuberculosis (Mtb) is the leading cause of death in the world from a bacterial infectious disease, affecting 1.8 billion people/year. This program examines the development of a new class of therapeutics that target the 4'-phosphopantetheinyltransferase (PPTase) PptT associated with mycolic acid production in Mycobacterium tuberculosis (Mtb) with the goal of identifying a panel of lead compounds within the funded period,