5DPX

1,2,4-Triazole-3-thione compounds as inhibitors of L1, di-zinc metallo-beta-lactamases.

5DPX の概要

• エントリーDOI: 10.2210/pdb5dpx/pdb
• 関連するPDBエントリー: 2FM6 2FU7 2FU8 2FU9 2GFJ 2GFK 2HB9
• 分子名称: Metallo-beta-lactamase L1 type 3, ZINC ION, 5-(2-methylphenyl)-3H-1,2,4-triazole-3-thione, ... (5 entities in total)
• 機能のキーワード: hydrolase, metallo, zn, lactamase
• 由来する生物種: Stenotrophomonas maltophilia (Pseudomonas maltophilia)
• 細胞内の位置: Periplasm : P52700
• タンパク質・核酸の鎖数: 2
• 化学式量合計: 58505.27

構造登録者

Nauton, L.,Garau, G.,Khan, R.,Dideberg, O. (登録日: 2015-09-14, 公開日: 2017-01-11, 最終更新日: 2024-11-13)

主引用文献

Sevaille, L.,Gavara, L.,Bebrone, C.,De Luca, F.,Nauton, L.,Achard, M.,Mercuri, P.,Tanfoni, S.,Borgianni, L.,Guyon, C.,Lonjon, P.,Turan-Zitouni, G.,Dzieciolowski, J.,Becker, K.,Benard, L.,Condon, C.,Maillard, L.,Martinez, J.,Frere, J.M.,Dideberg, O.,Galleni, M.,Docquier, J.D.,Hernandez, J.F.
1,2,4-Triazole-3-thione Compounds as Inhibitors of Dizinc Metallo-beta-lactamases.
ChemMedChem, 12:972-985, 2017

PubMed Abstract: Metallo-β-lactamases (MBLs) cause resistance of Gram-negative bacteria to β-lactam antibiotics and are of serious concern, because they can inactivate the last-resort carbapenems and because MBL inhibitors of clinical value are still lacking. We previously identified the original binding mode of 4-amino-2,4-dihydro-5-(2-methylphenyl)-3H-1,2,4-triazole-3-thione (compound IIIA) within the dizinc active site of the L1 MBL. Herein we present the crystallographic structure of a complex of L1 with the corresponding non-amino compound IIIB (1,2-dihydro-5-(2-methylphenyl)-3H-1,2,4-triazole-3-thione). Unexpectedly, the binding mode of IIIB was similar but reverse to that of IIIA. The 3 D structures suggested that the triazole-thione scaffold was suitable to bind to the catalytic site of dizinc metalloenzymes. On the basis of these results, we synthesized 54 analogues of IIIA or IIIB. Nineteen showed IC values in the micromolar range toward at least one of five representative MBLs (i.e., L1, VIM-4, VIM-2, NDM-1, and IMP-1). Five of these exhibited a significant inhibition of at least four enzymes, including NDM-1, VIM-2, and IMP-1. Active compounds mainly featured either halogen or bulky bicyclic aryl substituents. Finally, some compounds were also tested on several microbial dinuclear zinc-dependent hydrolases belonging to the MBL-fold superfamily (i.e., endonucleases and glyoxalase II) to explore their activity toward structurally similar but functionally distinct enzymes. Whereas the bacterial tRNases were not inhibited, the best IC values toward plasmodial glyoxalase II were in the 10 μm range.

PubMed: 28505394
DOI: 10.1002/cmdc.201700186

実験手法

X-RAY DIFFRACTION (1.85 Å)