InhA, the enoyl reductase enzyme from Mycobacterium tuberculosis (MTB), catalyzes the last step in the fatty acid biosynthesis pathway (FAS II). Frontline anti-tuberculosis drugs such as isoniazid (INH) target this enzyme. Drug resistance to INH results primarily from mutations in KatG, the enzyme that activates INH. Consequently, InhA inhibitors that do not require activation by KatG are attractive candidates for drug discovery. One such inhibitor is our lead compound for SAR studies triclosan, a common antibacterial additive in personal care products. Triclosan is a μM inhibitor of InhA and a pM inhibitor of the enoyl reductase from E. coli (FabI). Using structural and mechanistic data, we have developed a series of aliphatic-substituted triclosan analogs with a nM affinity for InhA and with sub-μM MIC99 values for H37Rv MTB. These compounds are currently being evaluated in an animal model of tuberculosis. Second generation analogues are now being developed to investigate and address compound bioavailability and cell membrane permeability.
Back to Biochemistry Poster Session
Back to The 33rd Northeast Regional Meeting (July 14-17, 2005)