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
  • 1. Novartis Institute for Tropical Diseases, 138670 Singapore, Singapore. Yong Loo Lin School of Medicine, National University of Singapore, 119228 Singapore, Singapore. [email protected] [email protected].
  • 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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