Structures of Mtb proteins conferring susceptibility to known Mtb inhibitors

描述（由申请人提供）：本项目的总体目标是确定抑制结核分枝杆菌（Mtb）和其他病原菌生长的潜在药物靶标和伴随抑制剂，以便为抗菌药物发现奠定基础。我们将通过鉴定Mtb全细胞生长抑制剂靶向的蛋白质来实现这一目标，该蛋白质是通过最近对20多万种药物样小分子进行的高通量筛选发现的。作为抑制剂靶标的蛋白质将通过遗传和互补生物化学方法鉴定。将与蛋白质结构倡议大规模中心合作，确定作为抑制剂靶点的结核分枝杆菌蛋白质或这些蛋白质的同源物的结构。在人类同源物可用的情况下，也将确定该结构或相关真核蛋白质的结构。结构信息和抑制剂身份将与相关蛋白的注释一起沿着使用，以提示每个靶蛋白的分子功能。将对这些分子功能进行测定，以确认功能和抑制作用。一旦确定了靶点，将另外分析其抑制剂对其他病原菌和真核细胞系的活性。然后将根据其新奇、伴随生长抑制剂的活性谱和抑制剂的效力对靶标进行优先排序。在五年的资助期间，我们预计将确认约200个顶级全细胞活性分子的分子靶点，并获得这些靶蛋白或相同序列家族成员的结构。这些结构、转运蛋白-蛋白质对和有关蛋白质的生化信息将为结核分枝杆菌药物发现提供丰富的先导化合物和生物化学资源，为理解结核分枝杆菌生物学奠定基础，并为通过治愈结核病改善人类健康提供前进的道路。

DESCRIPTION (provided by applicant): 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 eukaryotic 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 to 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.