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Manjunatha, Ujjini H; S Rao, Srinivasa P; Kondreddi, Ravinder Reddy; Noble, Christian G; Camacho, Luis R; Tan, Bee H; Ng, Seow H; Ng, Pearly Shuyi; Ma, Ng L; Lakshminarayana, Suresh B; Herve, Maxime; Barnes, Susan W; Yu, Weixuan; Kuhen, Kelli; Blasco, Francesca; Beer, David; Walker, John R; Tonge, Peter J; Glynne, Richard; Smith, Paul W; Diagana, Thierry T
Science translational medicine, 2015-Jan-07, Volume: 7, Issue: 269Journal Article
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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