U. Manjunatha, Srinivasa P. S. Rao, R. R. Kondreddi
Jan 7, 2015
Citations
4
Influential Citations
93
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Journal
Science Translational Medicine
Abstract
4-Hydroxy-2-pyridones, direct inhibitors of the mycobacterial protein InhA, are active against multidrug-resistant Mycobacterium tuberculosis. “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. New chemotherapeutic agents are urgently required to combat the global spread of multidrug-resistant tuberculosis (MDR-TB). The mycobacterial enoyl reductase InhA is one of the few clinically validated targets in tuberculosis drug discovery. We report the identification of a new class of direct InhA inhibitors, the 4-hydroxy-2-pyridones, using phenotypic high-throughput whole-cell screening. This class of orally active compounds showed potent bactericidal activity against common isoniazid-resistant TB clinical isolates. Biophysical studies revealed that 4-hydroxy-2-pyridones bound specifically to InhA in an NADH (reduced form of nicotinamide adenine dinucleotide)–dependent manner and blocked the enoyl substrate–binding pocket. The lead compound NITD-916 directly blocked InhA in a dose-dependent manner and showed in vivo efficacy in acute and established mouse models of Mycobacterium tuberculosis infection. Collectively, our structural and biochemical data open up new avenues for rational structure-guided optimization of the 4-hydroxy-2-pyridone class of compounds for the treatment of MDR-TB.