RT Journal Article SR Electronic T1 Direct inhibitors of InhA are active against Mycobacterium tuberculosis JF Science Translational Medicine FD American Association for the Advancement of Science SP 269ra3 OP 269ra3 DO 10.1126/scitranslmed.3010597 VO 7 IS 269 A1 Manjunatha, Ujjini H. A1 S. Rao, Srinivasa P. A1 Kondreddi, Ravinder Reddy A1 Noble, Christian G. A1 Camacho, Luis R. A1 Tan, Bee H. A1 Ng, Seow H. A1 Ng, Pearly Shuyi A1 Ma, Ng L. A1 Lakshminarayana, Suresh B. A1 Herve, Maxime A1 Barnes, Susan W. A1 Yu, Weixuan A1 Kuhen, Kelli A1 Blasco, Francesca A1 Beer, David A1 Walker, John R. A1 Tonge, Peter J. A1 Glynne, Richard A1 Smith, Paul W. A1 Diagana, Thierry T. YR 2015 UL http://stm.sciencemag.org/content/7/269/269ra3.abstract AB 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.