INHIBITOR STUDIES ON MYCOBACTERIUM TUBERCULOSIS MALATE SYNTHASE

摘要

The emergence of multidrug-resistant strains of Mycobacterium tuberculosis (Mtb) has intensified efforts to discover novel drugs for tuberculosis (TB) treatment. Targeting the persistent state of Mtb, a condition in which Mtb is resistant to conventional drug therapies, is of particular interest. Persistent bacteria rely on metabolic pathways that are distinct from active infection Mtb as the environmental conditions of the persistent state are different (e.g., low nutrient). Because persistent Mtb are forced to survive in a low nutrient environment, a short, two enzyme pathway that becomes heavily utilized and upregulated is the glyoxylate shunt. Since the glyoxylate shunt enzymes are not present in mammals, they make attractive drug targets. We are studying malate synthase (MS), one of the enzymes in the glyoxylate shunt. We used computational, biochemical, and cellular techniques to identify potential inhibitors of MS. Crystal structures of MS in complex with inhibitors were used to rationally design better MS inhibitors. MS inhibitors validated via an enzyme activity assay, were then tested against whole cells using a non-pathogenic form of mycobacteria, Mycobacterium smegmatis. In this manner, inhibitors against MS have been identified and characterized for further development into potential novel antitubercular drugs.