Structural Genomics of Persistence Targets from M. tuberculosis

描述(申请人提供)：结核病感染了世界三分之二的人口。尽管有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流行日益严重，这促进了潜伏性结核病向活动性疾病的转化，以及治愈结核病所需的漫长而复杂的化疗，这导致了普遍的不遵守规定。通过缩短化疗持续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以休眠、非复制的状态存在，在杀伤性药物和/或先天和适应性杀伤机制面前持续存在。因此，开发新的药物，无论是杀死这些持久性生物，抑制细菌进入持久性阶段，还是将持久性细菌转化为对我们目前的药物敏感的活跃生长的细胞，都将产生积极的效果。我们正在采取一种多学科的方法，将确定和描述对持续性结核分枝杆菌至关重要的新药靶点。靶标将接受一系列分析，包括微阵列实验、生物信息学和遗传技术，以确定来自结核分枝杆菌的潜在药物靶标的优先顺序，以便进行结构分析。首要目标将由我们的科学顾问小组确定并确定优先顺序，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或TBSGC实验室之一。我们的核心结构基因组学流水线将与各个实验室合作，生产目标蛋白质的衍射级晶体，结构分析将由各个实验室完成。我们还在该计划项目中拥有功能分析和虚拟配体筛选的能力，以确定用于靶向验证的新型抑制剂。我们的总体目标是通过结核病研究社区推动结构基因组学，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，开发结核病研究的中央储存库，并为未来先导化合物的开发发现药物靶标的化学抑制剂。

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.