Structure-Based Discovery of Critical Vulnerabilities of Mycobacteria
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abstract
The TB Structural Genomics Consortium (TBSGC) is a collaborative research group that hasstudied TB’s causative organism, Mycobacterium tuberculosis (Mtb), for the past 15 years. Overthe years we have focused our goals to concentrate on proteins that are drug targets for novelantibiotics, and proteins whose structure might contribute to our knowledge of vulnerabilities inMtb. We also supplemented our structural work with both chemistry and genetics to validate ourtargets, to obtain and optimize protein inhibitors, and to determine their underlying biological roleswithin Mtb. Our multidisciplinary approach has allowed us to add considerable knowledge tomycobacterial 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 drugdevelopers.In this TBSGC renewal, we propose to incorporate new innovative technologies, includingmembrane protein structures and cryo-EM, to strengthen our commitment to TB drugdevelopment. We will leverage structure determination to both understand function and identifypotential small molecule inhibitors. The fundamental goal of this project is to accelerate TB drugdiscovery by understanding essential functions of the mycobacterial cell and providing validatedtargets and inhibitors to our partners in the TB drug development community.
