Direct inhibitors of InhA are active against Mycobacterium tuberculosis.
Sci Transl Med, 2015/1/07;7(269):269ra3.
Manjunatha UH[1], S Rao SP[2], Kondreddi RR[2], Noble CG[2], Camacho LR[2], Tan BH[2], Ng SH[2], Ng PS[2], Ma NL[2], Lakshminarayana SB[2], Herve M[2], Barnes SW[3], Yu W[4], Kuhen K[3], Blasco F[2], Beer D[2], Walker JR[3], Tonge PJ[4], Glynne R[3], Smith PW[2], Diagana TT[1]
Affiliations
PMID: 25568071DOI: 10.1126/scitranslmed.3010597
Impact factor: 19.319
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.
MeSH terms
Animals; Antitubercular Agents; Bacterial Proteins; Biophysical Phenomena; Crystallography, X-Ray; Disease Models, Animal; Drug Resistance, Multiple, Bacterial; Enzyme Inhibitors; Mice, Inbred BALB C; Models, Molecular; Mycobacterium tuberculosis; Oxidoreductases; Pyridines; Reproducibility of Results; Sequence Analysis, DNA; Tuberculosis, Multidrug-Resistant
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