Discovery of antitubercular PptT inhibitors

描述（由申请方提供）：该项目旨在鉴定与结核分枝杆菌（Mtb）中分枝菌酸产生相关的4 '-磷酸泛酰巯基乙胺基转移酶（PPTase）PptT的抑制剂。PptT负责激活分枝菌酸合酶，分枝菌酸合酶是参与分枝杆菌细胞壁生物合成的必需蛋白质，也是新验证的药物靶点。我们最近完成了一项高通量筛选（HTS）的努力，以确定对Sfp，枯草芽孢杆菌表面活性素PPT酶的抑制剂，与美国国立卫生研究院化学基因组学中心（NCGC）合作。在这里，我们试图探测在该筛选中鉴定的命中物对PptT的活性，并评估它们对野生型和耐药Mtb菌株的抗菌活性。考虑到我们从Sfp HTS努力中获得的初步结果，一种稳健和通用的PPTase测定法的开发，这种病原体对药物开发的重要性，以及PptT作为具有抗生素开发潜力的可药用靶标的最近验证，我们预计在该项目的时间范围内发现一类新的抗结核化合物。 公共卫生相关性：结核分枝杆菌（Mycobacterium tuberculosis，Mtb）是世界上由细菌感染性疾病引起的主要死亡原因，每年影响18亿人。该项目研究了一类新的治疗药物的开发，这些药物靶向与结核分枝杆菌（Mtb）中分枝菌酸产生相关的4 '-磷酸泛酰巯基乙胺基转移酶（PPTase）PptT，目的是在资助期内鉴定一组先导化合物，

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,