Structure-based Discovery of Critical Vulnerabilities of Mycobacteria

基于结构的分枝杆菌关键漏洞发现

基本信息

批准号：
10242858
负责人：
JAMES C SACCHETTINI
金额：
$ 240.73万
依托单位：
TEXAS A&M AGRILIFE RESEARCH
依托单位国家：
美国
项目类别：
财政年份：
2012
资助国家：
美国
起止时间：
2012-09-01 至 2023-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10242858
关键词：
Adopted Animals Antibiotics Binding Biochemical Biological Biological Assay Biology Cells Chemistry Communication Community Developments Complex Cryoelectron Microscopy Development Drug Targeting Enzymes Genetic Genomics Genus Mycobacterium Goals Knowledge Macromolecular Complexes Mediating Membrane Membrane Proteins Membrane Transport Proteins Metabolic Multienzyme Complexes Mycobacterium tuberculosis National Institute of Allergy and Infectious Disease Organism Proteins Research Resources Ribosomes Role Siderophores Specificity Structure Supervision Translations Virulence Work base chemical genetics drug development drug discovery flexibility genetic information improved inhibitor/antagonist innovative technologies interdisciplinary approach mycobacterial new therapeutic target novel preclinical development programs protein structure small molecule small molecule inhibitor structural biology structural genomics tuberculosis drugs

项目摘要

Project Summary – Overall The TB Structural Genomics Consortium (TBSGC) is a collaborative research group that has studied TB’s causative organism, Mycobacterium tuberculosis (Mtb), for the past 15 years. Over the years we have focused our goals to concentrate on proteins that are drug targets for novel antibiotics, and proteins whose structure might contribute to our knowledge of vulnerabilities in Mtb. We also supplemented our structural work with both chemistry and genetics to validate our targets, to obtain and optimize protein inhibitors, and to determine their underlying biological roles within Mtb. Our multidisciplinary approach has allowed us to add considerable knowledge to mycobacterial structures, and to leverage this information to inform drug development. Significantly, results of the last TBSGC cycle has led to a novel anti-TB drug that is in late pre- clinical development along with others compounds that have been adopted by anti-TB drug developers. In this TBSGC renewal, we propose to incorporate new innovative technologies, including membrane protein structures and cryo-EM, to strengthen our commitment to TB drug development. We will leverage structure determination to both understand function and identify potential small molecule inhibitors. The fundamental goal of this project is to accelerate TB drug discovery by understanding essential functions of the mycobacterial cell and providing validated targets and inhibitors to our partners in the TB drug development community.

项目总结 – 总体结核病结构基因组学联盟 (TBSGC) 是一个合作研究小组，在过去 15 年里，我们一直在研究结核病的致病菌——结核分枝杆菌 (Mtb)。多年来，我们将目标集中在作为新型药物靶点的蛋白质上。抗生素和蛋白质的结构可能有助于我们了解细菌的脆弱性我们还用化学和遗传学补充了我们的结构工作，以验证我们的结果。目标，获得和优化蛋白质抑制剂，并确定其潜在的生物学作用在 Mtb 中，我们的多学科方法使我们能够增加大量的知识。分枝杆菌结构，并利用这些信息为药物开发提供信息。值得注意的是，上一个 TBSGC 周期的结果已经产生了一种新型抗结核药物，该药物处于后期阶段。与其他已被抗结核药物采用的化合物一起进行临床开发开发商。在本次 TBSGC 更新中，我们建议纳入新的创新技术，包括膜蛋白结构和冷冻电镜，加强我们对结核病药物的承诺我们将利用结构确定来理解功能并识别。该项目的根本目标是加速结核病药物的研发。通过了解分枝杆菌细胞的基本功能并提供经过验证的发现为我们结核病药物开发界的合作伙伴提供靶点和抑制剂。