RT Journal Article
SR Electronic
T1 Direct inhibitors of InhA are active against <em>Mycobacterium tuberculosis</em>
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.