Structural Genomics of Persistence Targets from M. tuberculosis

描述（由申请人提供）：结核病（TB）感染了世界三分之二的人口。尽管已有40年的药物可以治愈结核病，但它仍在以显著的速度增长。这主要是由于艾滋病毒日益流行，使潜伏性结核病容易转化为活动性结核病，而治愈结核病需要长期和复杂的化疗，这导致普遍不遵守规定。通过缩短化疗时间来减少不依从性将对结核病控制产生重大影响。在感染中，一小部分结核分枝杆菌处于休眠、不复制状态，在面对杀毒药物和/或先天和适应性杀伤机制时仍然存在。因此，开发新的药物，要么杀死这些持续存在的有机体，要么抑制杆菌进入持续阶段，要么将持续存在的杆菌转化为对我们现有药物敏感的积极生长的细胞，将会产生积极的影响。我们正在采取一种多学科的方法，以确定和表征对持久性结核分枝杆菌至关重要的新药物靶点。靶标将暴露于一系列分析中，包括微阵列实验、生物信息学和遗传技术，以优先考虑结核分枝杆菌的潜在药物靶标进行结构分析。顶级目标将由我们的科学顾问小组确定并优先考虑，并根据他们的兴趣水平，专业知识和可用资源分配给计划项目的一个实验室或TBSGC实验室。我们的核心结构基因组学管道将与单个实验室合作，生产目标蛋白质的衍射质量晶体，结构分析将由单个实验室完成。我们还在项目项目中具有功能分析和虚拟配体筛选的能力，以确定用于目标验证的新型抑制剂。我们的总体目标是利用结核病研究界推动结构基因组学，特别是与持久性相关的结构基因组学，增加对结核分枝杆菌发病机制的了解，为结核病研究开发一个中央储存库，并发现药物靶点的化学抑制剂，以用于未来先导化合物的开发。

DESCRIPTION (provided by applicant): Tuberculosis (TB) infects two-thirds of the world population. Despite forty years of drugs that can cure TB, it continues to increase at a significant rate. This is primarily due to the growing HIV epidemic, which facilitates the conversion of latent TB to the active disease, and the long and complicated chemotherapy required to cure TB, which results in widespread non-compliance. Reducing non-compliance, by reducing the duration of chemotherapy will have a great impact on TB control. In an infection, a fraction of Mycobacterium tuberculosis exist in a dormant, non-replicating state that persists in the face of cidal drugs and/or innate and adaptive killing mechanisms. Therefore, the development of new drugs that either kill these persisting organisms, inhibit bacilli from entering the persistent phase, or convert the persistent bacilli into actively growing cells susceptible to our current drugs will have a positive effect. We are taking a multi-discipline approach that will identify and characterize new drug targets that are essential for persistent M. tuberculosis. Targets will be exposed to a battery of analyses including microarray experiments, bioinformatics, and genetic techniques to prioritize potential drug targets from Mtb for structural analysis. Top targets will be identified and prioritized by our scientific advisory panel, and allocated to one of the laboratories the Program Project or a TBSGC laboratory based on their level of interest, expertise and available resources. Our Core structural genomics pipeline will work with the individual laboratories to produce diffraction quality crystals of targeted proteins, and structural analyses will be completed by the individual laboratories. We also have in the Program Project the capabilities for functional analysis, and virtual ligand screening to identify novel inhibitors for target validation. Our overarching goals are to increase the knowledge of Mtb pathogenesis using the TB research community to drive structural genomics, particularly related to persistence, develop a central repository forTB research, and discover chemical inhibitors of drug targets for future development of lead compounds.