Structures of Mtb proteins conferring susceptibility to known Mtb inhibitors

该项目的总体目标是确定潜在的药物靶点和抑制作用的伴随抑制剂 结核分枝杆菌（Mtb）等致病菌的生长，以发展为基础 用于抗菌药物的发现。我们将通过识别蛋白质来实现这一目标，这些蛋白质是由整个 最近进行的高通量筛选发现了Mtb的细胞生长抑制剂， 药物样小分子。作为抑制剂靶点的蛋白质将通过遗传和 互补的生物化学方法。将与蛋白质组合作确定结构 作为抑制剂或同源物靶点的Mtb蛋白的结构倡议大规模中心 这些蛋白质。在人类同源物可用的情况下，该结构或相关的 真核蛋白也将被测定。将使用结构信息和抑制剂身份 沿着相关蛋白的注释以提示每个靶蛋白的分子功能。测定 将对这些分子的功能进行验证，以确认功能和抑制。一旦目标 将另外分析鉴定的它们的抑制剂对其它病原菌的活性， 真核细胞系然后，将根据目标的新奇、 伴随生长抑制剂和抑制剂的效力。在五年的补助金期间，我们预计 确定了约200个顶级全细胞活性分子的分子靶标，并获得了结构 这些靶蛋白或相同序列家族的成员。这些结构，即通道蛋白对， 蛋白质的生物化学信息将提供丰富的先导化合物资源， 结核分枝杆菌药物发现的生物化学，理解结核分枝杆菌生物学的基础，以及 通过治疗肺结核来改善人类健康的努力。

The overall goal of this project is to identify potential drug targets and companion inhibitors that inhibit growth of Mycobacterium tuberculosis (Mtb), and other pathogenic bacteria in order to develop a foundation for antimicrobial drug discovery. We will accomplish this by identifying proteins that are targeted by whole cell growth inhibitors of Mtb discovered by a recently conducted high-throughput screen of over 200,000 drug-like small molecules. Proteins that are targets of inhibitors will be identified by genetic and complementary biochemical approaches. Structures will be determined, in collaboration with the Protein Structure Initiative Large-Scale Centers, of either the Mtb proteins that are targets of inhibitors or homologs of these proteins. In cases where a human homolog is available, that structure or that of a related eucaryotic protein will be determined as well. The structural information and inhibitor identities will be used along with annotations of related proteins to suggest molecular functions for each target protein. Assays for these molecular functions will be carried out to confirm both function and inhibition. Once targets are identified their inhibitors will additionally be analyzed for their activity against other pathogenic bacteria and eukaryotic cell lines. The targets will then be prioritized based on their novelty, the spectrum of activity of the companion growth inhibitor and the potency of the inhibitor. During the five years of the grant we expect confirm the molecular targets for about 200 of the top whole cell active molecules and obtain the structures of these target proteins or members of the same sequence family. These structures, inhibitor-protein pairs, and biochemical information about the proteins will provide a rich resource of lead compounds and biochemistry for Mtb drug discovery, a foundation for understanding Mtb biology, and a path forward in the effort to improve human health by curing tuberculosis.