The ability of Mycobacterium tuberculosis (Mtb) to metabolize cholesterol is critical for the maintenance of the Mtb infection in the host. We identified two new structural-functional motifs for catalysis of beta-oxidation with steroid substrates in the igr operon that function in the metabolic pathway for sterol side-chain cleavage. These enzymes form unusual heterotetramers. A fuller bioinformatic analysis of the Mtb genome has identified additional heteromeric complexes that are encoded by cholesterol-regulated genes and enabled further mapping of the pathways. Using a privileged pharmacophore, we have identified lead compounds that show excellent antibacterial activity against Mycobacterium tuberculosis under both aerobic and anaerobic growth conditions and that enhance bactericidal activity.

Co-therapy strategy to enhance target vulnerability in Mycobacterium tuberculosis

253rd National Meeting (2017)

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