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Sci Transl Med. 2015 Jan 7;7(269):269ra3. doi: 10.1126/scitranslmed.3010597.

Direct inhibitors of InhA are active against Mycobacterium tuberculosis.

Author information

1
Novartis Institute for Tropical Diseases, 138670 Singapore, Singapore. Yong Loo Lin School of Medicine, National University of Singapore, 119228 Singapore, Singapore. manjunatha.ujjini@novartis.com thierry.diagana@novartis.com.
2
Novartis Institute for Tropical Diseases, 138670 Singapore, Singapore.
3
Genomics Institute of the Novartis Research Foundation, San Diego, CA 92121, USA.
4
Institute of Chemical Biology & Drug Discovery, Stony Brook University, Stony Brook, NY 11794-3400, USA.

Abstract

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.

PMID:
25568071
PMCID:
PMC4383039
DOI:
10.1126/scitranslmed.3010597
[Indexed for MEDLINE]
Free PMC Article

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