Structural Genomics of Persistence Targets from M. tuberculosis

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DESCRIPTION (provided by applicant): Tuberculosis (TB) infects two-thirds of the world population. Despite forty years of drugs that can cure TB, it continues to increase at a significant rate. This is primarily due to the growing HIV epidemic, which facilitates the conversion of latent TB to the active disease, and the long and complicated chemotherapy required to cure TB, which results in widespread non-compliance. Reducing non-compliance, by reducing the duration of chemotherapy will have a great impact on TB control. In an infection, a fraction of Mycobacterium tuberculosis exist in a dormant, non-replicating state that persists in the face of cidal drugs and/or innate and adaptive killing mechanisms. Therefore, the development of new drugs that either kill these persisting organisms, inhibit bacilli from entering the persistent phase, or convert the persistent bacilli into actively growing cells susceptible to our current drugs will have a positive effect. We are taking a multi-discipline approach that will identify and characterize new drug targets that are essential for persistent M. tuberculosis. Targets will be exposed to a battery of analyses including microarray experiments, bioinformatics, and genetic techniques to prioritize potential drug targets from Mtb for structural analysis. Top targets will be identified and prioritized by our scientific advisory panel, and allocated to one of the laboratories the Program Project or a TBSGC laboratory based on their level of interest, expertise and available resources. Our Core structural genomics pipeline will work with the individual laboratories to produce diffraction quality crystals of targeted proteins, and structural analyses will be completed by the individual laboratories. We also have in the Program Project the capabilities for functional analysis, and virtual ligand screening to identify novel inhibitors for target validation. Our overarching goals are to increase the knowledge of Mtb pathogenesis using the TB research community to drive structural genomics, particularly related to persistence, develop a central repository forTB research, and discover chemical inhibitors of drug targets for future development of lead compounds.