Research ArticleTuberculosis

Direct inhibitors of InhA are active against Mycobacterium tuberculosis

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Science Translational Medicine  07 Jan 2015:
Vol. 7, Issue 269, pp. 269ra3
DOI: 10.1126/scitranslmed.3010597

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“Rediscovering” InhA for Treating TB

Isoniazid, a key component of the drug combination currently used to treat tuberculosis, inhibits the Mycobacterium tuberculosis InhA enzyme. Unfortunately, isoniazid has been rendered increasingly obsolete with the spread of multidrug-resistant tuberculosis (MDR-TB). Through phenotypic screening and subsequent target identification, Manjunatha et al. discovered 4-hydroxy-2-pyridones, a new class of InhA inhibitors. Their direct mode of binding to InhA circumvents the main mechanisms of isoniazid resistance, and these compounds showed activity against a number of MDR-TB clinical isolates. Preliminary medicinal chemistry efforts yielded a lead compound NITD-916 that displayed potent oral activity in mouse models of tuberculosis. The structural data presented in this new study provide a path for further optimization of 4-hydroxy-2-pyridones through rational design.

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