2. Academic Validation
  3. Direct inhibitors of InhA are active against Mycobacterium tuberculosis

Direct inhibitors of InhA are active against Mycobacterium tuberculosis

  • Sci Transl Med. 2015 Jan 7;7(269):269ra3. doi: 10.1126/scitranslmed.3010597.
Ujjini H Manjunatha 1,  Srinivasa P S Rao 2,  Ravinder Reddy Kondreddi 2,  Christian G Noble 2,  Luis R Camacho 2,  Bee H Tan 2,  Seow H Ng 2,  Pearly Shuyi Ng 2,  Ng L Ma 2,  Suresh B Lakshminarayana 2,  Maxime Herve 2,  Susan W Barnes 3,  Weixuan Yu 4,  Kelli Kuhen 3,  Francesca Blasco 2,  David Beer 2,  John R Walker 3,  Peter J Tonge 4,  Richard Glynne 3,  Paul W Smith 2,  Thierry T Diagana 1
Affiliations

Affiliations

  • 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.
PMID: 25568071 DOI: 10.1126/scitranslmed.3010597
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.

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