Screen for Mycobacterium Tuberculosis (RMI)

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DESCRIPTION (provided by applicant): It is estimated that one third of the world's population is infected with tuberculosis (TB), with about 8 million new cases annually. Multi-drug resistant TB, defined as forms resistant to two or more of the front line anti-TB agents, has become an increasing health problem, especially in HIV infected individuals. These forms of TB are more often fatal and more difficult to treat. Consequently, development of molecular research tools or drugs targeting novel pathways has become increasingly important. The biosynthetic pathway of pantothenate is such a target. Pantothenate is an essential precursor in mycobacteria for the synthesis of co-enzyme A and acyl carrier protein which are involved in fatty acid synthesis. Pantothenate synthetase, encoded by the panC gene, catalyzes the formation of pantothenate in bacteria. M. tuberculosis pantothenate synthetase has been characterized enzymatically and a high resolution crystal structure has also been solved. More recently several compounds have been identified which inhibit this enzyme. Unfortunately, none of these compounds affect the growth of Mycobacterium tuberculosis in vitro. To address the need for molecular research tools to study the pantothenate pathway in M. tuberculosis the specific aims of this proposal are: 1) To transfer the existing HTS assay for pantothenate synthetase to the Molecular Libraries Screening Center Network. . 2) To follow up hits from the HTS assay in a series of confirmatory assays available through the TAACF that would evaluate their in vitro and in vivo efficacy against M. tuberculosis. 3) To study the effect of these novel inhibitors on the pantothenate pathway in M. smegmatis. 4) To co-crystallize these compounds with pantothenate synthetase to study their mode of binding