Discovery of antitubercular PptT inhibitors

描述（由申请人提供）：该项目旨在鉴定结核分枝杆菌（Mtb）中与霉菌酸产生相关的4'-磷酸腺苷基转移酶（PPTase） PptT抑制剂。PptT负责霉菌酸合成酶的激活，霉菌酸合成酶是一种参与分枝杆菌细胞壁生物合成的必需蛋白，也是一种新证实的药物靶点。我们最近与NIH化学基因组学中心（NCGC）合作完成了一项高通量筛选（HTS）工作，以确定枯草芽孢杆菌表面蛋白PPTase Sfp抑制剂。在这里，我们试图探索在这个筛选中发现的对PptT的活性，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。考虑到Sfp HTS的初步结果、PPTase检测的发展、该病原体对药物开发的重要性，以及PptT作为一种具有抗生素开发潜力的可药物靶点的最近验证，我们期待在这个项目的时间框架内发现一类新的抗小管化合物。

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,