Screen for Mycobacterium Tuberculosis (RMI)

描述（由申请人提供）：据估计，世界上三分之一的人口感染了结核病，每年约有800万新病例。耐多药结核病被定义为对两种或两种以上一线抗结核药物具有耐药性的结核病，它已成为一个日益严重的健康问题，特别是在艾滋病毒感染者中。这些形式的结核病往往更致命，也更难以治疗。因此，开发针对新途径的分子研究工具或药物变得越来越重要。泛酸盐的生物合成途径就是这样一个靶点。泛酸是分支杆菌合成辅酶A和酰基载体蛋白所必需的前体，辅酶A和酰基载体蛋白参与脂肪酸的合成。泛酸合成酶由panC基因编码，在细菌中催化泛酸的形成。对结核分枝杆菌泛酸合成酶进行了酶学表征，并解决了其高分辨率晶体结构。最近已经发现了几种抑制这种酶的化合物。不幸的是，这些化合物都不能影响结核分枝杆菌的体外生长。为了解决研究结核分枝杆菌泛酸途径的分子研究工具的需求，本提案的具体目标是：1)将现有的泛酸合成酶HTS检测转移到分子文库筛选中心网络。2)在TAACF提供的一系列验证性试验中跟踪HTS试验的结果，以评估其体外和体内抗结核分枝杆菌的功效。3)研究这些新型抑制剂对耻垢单胞菌泛酸途径的影响。4)将这些化合物与泛酸合成酶共结晶，研究其结合方式

DESCRIPTION (provided by applicant): It is estimated that one third of the world's population is infected with tuberculosis (TB), with about 8 million new cases annually. Multi-drug resistant TB, defined as forms resistant to two or more of the front line anti-TB agents, has become an increasing health problem, especially in HIV infected individuals. These forms of TB are more often fatal and more difficult to treat. Consequently, development of molecular research tools or drugs targeting novel pathways has become increasingly important. The biosynthetic pathway of pantothenate is such a target. Pantothenate is an essential precursor in mycobacteria for the synthesis of co-enzyme A and acyl carrier protein which are involved in fatty acid synthesis. Pantothenate synthetase, encoded by the panC gene, catalyzes the formation of pantothenate in bacteria. M. tuberculosis pantothenate synthetase has been characterized enzymatically and a high resolution crystal structure has also been solved. More recently several compounds have been identified which inhibit this enzyme. Unfortunately, none of these compounds affect the growth of Mycobacterium tuberculosis in vitro. To address the need for molecular research tools to study the pantothenate pathway in M. tuberculosis the specific aims of this proposal are: 1) To transfer the existing HTS assay for pantothenate synthetase to the Molecular Libraries Screening Center Network. . 2) To follow up hits from the HTS assay in a series of confirmatory assays available through the TAACF that would evaluate their in vitro and in vivo efficacy against M. tuberculosis. 3) To study the effect of these novel inhibitors on the pantothenate pathway in M. smegmatis. 4) To co-crystallize these compounds with pantothenate synthetase to study their mode of binding