7PP0

Crystal structure of the VIM-2 acquired metallo-beta-Lactamase in complex with compound 28 (JMV-7038)

7PP0 の概要

• エントリーDOI: 10.2210/pdb7pp0/pdb
• 分子名称: Metallo-beta-lactamase VIM-2-like protein, ZINC ION, ACETATE ION, ... (5 entities in total)
• 機能のキーワード: metallo-beta-lactamase, vim-2, triazole-thione, inhibitor, zinc, hydrolase
• 由来する生物種: Pseudomonas aeruginosa
• タンパク質・核酸の鎖数: 1
• 化学式量合計: 26308.18

構造登録者

Tassone, G.,Benvenuti, M.,Verdirosa, F.,Corsica, G.,Chelini, G.,De Luca, F.,Docquier, J.D.,Pozzi, C.,Mangani, S. (登録日: 2021-09-10, 公開日: 2022-03-16, 最終更新日: 2024-01-31)

主引用文献

Verdirosa, F.,Gavara, L.,Sevaille, L.,Tassone, G.,Corsica, G.,Legru, A.,Feller, G.,Chelini, G.,Mercuri, P.S.,Tanfoni, S.,Sannio, F.,Benvenuti, M.,Cerboni, G.,De Luca, F.,Bouajila, E.,Vo Hoang, Y.,Licznar-Fajardo, P.,Galleni, M.,Pozzi, C.,Mangani, S.,Docquier, J.D.,Hernandez, J.F.
1,2,4-Triazole-3-Thione Analogues with a 2-Ethylbenzoic Acid at Position 4 as VIM-type Metallo-beta-Lactamase Inhibitors.
Chemmedchem, 17:e202100699-e202100699, 2022

PubMed Abstract: Metallo-β-lactamases (MBLs) are increasingly involved as a major mechanism of resistance to carbapenems in relevant opportunistic Gram-negative pathogens. Unfortunately, clinically efficient MBL inhibitors still represent an unmet medical need. We previously reported several series of compounds based on the 1,2,4-triazole-3-thione scaffold. In particular, Schiff bases formed between diversely 5-substituted-4-amino compounds and 2-carboxybenzaldehyde were broad-spectrum inhibitors of VIM-type, NDM-1 and IMP-1 MBLs. Unfortunately, these compounds were unable to restore antibiotic susceptibility of MBL-producing bacteria, probably because of poor penetration and/or susceptibility to hydrolysis. To improve their microbiological activity, we synthesized and characterized compounds where the hydrazone-like bond of the Schiff base analogues was replaced by a stable ethyl link. This small change resulted in a narrower inhibition spectrum, as all compounds were poorly or not inhibiting NDM-1 and IMP-1, but showed a significantly better activity on VIM-type enzymes, with K values in the μM to sub-μM range. The resolution of the crystallographic structure of VIM-2 in complex with one of the best inhibitors yielded valuable information about their binding mode. Interestingly, several compounds were shown to restore the β-lactam susceptibility of VIM-type-producing E. coli laboratory strains and also of K. pneumoniae clinical isolates. In addition, selected compounds were found to be devoid of toxicity toward human cancer cells at high concentration, thus showing promising safety.

PubMed: 35050549
DOI: 10.1002/cmdc.202100699

実験手法

X-RAY DIFFRACTION (1.73 Å)