Development of modern InhA inhibitors to combat drug resistant strains of Mycobacterium tuberculosis

Strategies for the development of novel tuberculosis chemotherapeutics against existing drug resistant strains involve the identification and inhibition of novel drug targets as well as the design and synthesis of compounds against historical targets. InhA, the enoyl reductase from the mycobacterial type II fatty acid biosynthesis pathway, is a target of the frontline chemotherapeutic, isoniazid (INH). Importantly, the majority of INH-resistant clinical isolates arise from mutations in KatG, the enzyme responsible for activating isoniazid, into its active form. Thus compounds that inhibit InhA without first requiring KatG activation will be active against the majority of INH resistant strains of Mycobacterium tuberculosis. This review describes the role of InhA in cell wall biosynthesis and recent progress in the development of novel diphenyl ether-based InhA inhibitors that have activity against both sensitive and drug resistant strains of M. tuberculosis.