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。尽管有四十年的药物可以治愈结核病，但它继续以显着的速度增长。这主要是由于艾滋病毒流行的日益增长，这有利于潜伏性结核病转化为活动性疾病，以及治愈结核病所需的长期和复杂的化疗，这导致广泛的不遵守。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，一部分结核分枝杆菌以休眠、非复制状态存在，其在面对杀灭药物和/或先天和适应性杀伤机制时持续存在。因此，开发新的药物，杀死这些持续存在的生物体，抑制杆菌进入持续期，或将持续存在的杆菌转化为对我们目前的药物敏感的活跃生长的细胞，将产生积极的效果。我们正在采取多学科的方法，将确定和表征新的药物靶点，这是必不可少的持续M。结核目标将暴露于一系列分析，包括微阵列实验，生物信息学和遗传技术，以优先考虑来自Mtb的潜在药物靶点进行结构分析。我们的科学顾问小组将确定最高目标并进行优先排序，并根据其兴趣水平，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管道将与各个实验室合作，生产目标蛋白质的衍射质量晶体，结构分析将由各个实验室完成。我们在项目中还具有功能分析和虚拟配体筛选的能力，以识别用于靶点验证的新型抑制剂。我们的总体目标是增加结核病发病机制的知识，利用结核病研究界推动结构基因组学，特别是与持久性有关的结构基因组学，开发结核病研究的中央储存库，并发现药物靶点的化学抑制剂，用于未来开发先导化合物。

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.