4R9S

Mycobacterium tuberculosis InhA bound to NITD-916

4R9S の概要

• エントリーDOI: 10.2210/pdb4r9s/pdb
• 関連するPDBエントリー: 4R9R
• 分子名称: Enoyl-[acyl-carrier-protein] reductase [NADH], NICOTINAMIDE-ADENINE-DINUCLEOTIDE, 6-[(4,4-dimethylcyclohexyl)methyl]-4-hydroxy-3-phenylpyridin-2(1H)-one, ... (4 entities in total)
• 機能のキーワード: enoyl acyl carrier protein reductase, oxidoreductase
• 由来する生物種: Mycobacterium tuberculosis H37Rv
• タンパク質・核酸の鎖数: 4
• 化学式量合計: 119247.60

構造登録者

Noble, C.G. (登録日: 2014-09-07, 公開日: 2015-01-21, 最終更新日: 2023-11-08)

主引用文献

Manjunatha, U.H.,Rao, S.P.S.,Kondreddi, R.R.,Noble, C.G.,Camacho, L.R.,Tan, B.H.,Ng, S.H.,Ng, P.S.,Ma, N.L.,Lakshminarayana, S.B.,Herve, M.,Barnes, S.W.,Yu, W.,Kuhen, K.,Blasco, F.,Beer, D.,Walker, J.R.,Tonge, P.J.,Glynne, R.,Smith, P.W.,Diagana, T.T.
Direct inhibitors of InhA are active against Mycobacterium tuberculosis
Sci Transl Med, 7:269ra3-269ra3, 2015

PubMed 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.

PubMed: 25568071
DOI: 10.1126/scitranslmed.3010597

実験手法

X-RAY DIFFRACTION (3.2 Å)