Abstract
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.
Keywords: InhA, enoyl reductase, fatty acid biosynthesis, mycolic acid, cell wall, mycobacterium, isoniazid, diphenyl ether, triclosan
Current Topics in Medicinal Chemistry
Title: Development of Modern InhA Inhibitors to Combat Drug Resistant Strains of Mycobacterium tuberculosis
Volume: 7 Issue: 5
Author(s): Peter J. Tonge, Caroline Kisker and Richard A. Slayden
Affiliation:
Keywords: InhA, enoyl reductase, fatty acid biosynthesis, mycolic acid, cell wall, mycobacterium, isoniazid, diphenyl ether, triclosan
Abstract: 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.
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Cite this article as:
Tonge J. Peter, Kisker Caroline and Slayden A. Richard, Development of Modern InhA Inhibitors to Combat Drug Resistant Strains of Mycobacterium tuberculosis, Current Topics in Medicinal Chemistry 2007; 7 (5) . https://dx.doi.org/10.2174/156802607780059781
DOI https://dx.doi.org/10.2174/156802607780059781 |
Print ISSN 1568-0266 |
Publisher Name Bentham Science Publisher |
Online ISSN 1873-4294 |
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