Structure-based Discovery of Critical Vulnerabilities of Mycobacteria

基于结构的分枝杆菌关键漏洞发现

• 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
• 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

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.

项目摘要-整体