Structure-based Discovery of Critical Vulnerabilities of Mycobacteria

项目摘要--总体 结核病结构基因组学联盟(TBSGC)是一个合作研究组织，它拥有 在过去的15年里，研究了结核病的病原体--结核分枝杆菌(Mtb)。完毕 多年来，我们一直将目标集中在作为新药靶点的蛋白质上 抗生素和蛋白质，它们的结构可能有助于我们了解 山地车。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 靶点，以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内。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，并利用这些信息来为药物开发提供信息。 值得注意的是，上一次TBSGC周期的结果导致了一种新的抗结核病药物，该药物处于晚期 抗结核药物采用的其他化合物的临床进展 开发商。 在此次TBSGC续期中，我们建议采用新的创新技术，包括 膜蛋白结构和冷冻-EM，以加强我们对结核病药物的承诺 发展。我们将利用结构决定来理解功能和确定 潜在的小分子抑制剂。这个项目的基本目标是加速治疗结核病的药物 通过了解分枝杆菌细胞的基本功能并提供经过验证的 向我们在结核病药物开发界的合作伙伴提供靶标和抑制剂。

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.