Structure-based Discovery of Critical Vulnerabilities of Micobacteria

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DESCRIPTION OF THE OVERALL PROGRAM (provided by applicant): The overall mission of the TB Structural Genomics Consortium is to determine the three-dimensional structures of proteins from M. tuberculosis (Mtb), prioritized by their relevance for drug discovery. Mtb, the causative agent of tuberculosis, remains a major-health threat worldwide, and structural information on relevant proteins is critically needed to support future drug discovery. Our Program Project focuses not only on solving structures of proteins in vulnerable pathways, but also complexes of drug targets with inhibitors bound, which will yield important insights about active-site interactions for drug design. Each of the four projects has chosen to focus on targets and processes that are essential to survival in the host. Project 1 (UCB: PI: Alber) is focused on defining new mechanistic paradigms to Mtb cell-wall biosynthesis and remodeling processes that are essential for cell growth and division. Project 2 (TAMU: PI: Sacchettini) will solve the crystal structures of core metabolic enzymes, including those involved in energy production, biosynthesis of amino acids and co-factors, and biosynthesis of lipid components of the cell wall. Project 3 (UCLA: Pi: Eisenberg) will investigate structures of families of protein complexes, including PE/PPE and ESX proteins, as well as toxin/anti-toxin pairs. Project 4 (UCI, PI: Goulding) will focus on structural characterization of proteins involved in metabolite transport and disulfide-bond isomerization. A novel aspect of our approach is the use of the two Core projects to aid our group projects in structure determination and to gain valuable biological information for their targets. Our Structure Determination Core will produce recombinant protein and crystals, and determine their structures through a high-efficiency pipeline. Our Chemical and Genetic Core will use genetic methods to evaluate the essentiality, function, and interactions of individual targets and also conduct HTS to identify small-molecule inhibitors of our targets. The inhibitors will serve as ligands for co-crystallizatin, and will be valuable chemical tools for probing function in cells and validating targets. All of th structural and biochemical data we collect will be provided to the public; to foster future drug discovery efforts in the academic and pharmaceutical industries.