7DZ1

Crystal structure of VIM-2 MBL in complex with 1-benzyl-5-methyl-1H-imidazole-2-carboxylic acid

7DZ1 の概要

• エントリーDOI: 10.2210/pdb7dz1/pdb
• 分子名称: Beta-lactamase class B VIM-2, ZINC ION, 5-methyl-1-(phenylmethyl)imidazole-2-carboxylic acid, ... (4 entities in total)
• 機能のキーワード: metallo-beta-lactamase vim-2, vim-2, hydrolase
• 由来する生物種: Pseudomonas aeruginosa
• タンパク質・核酸の鎖数: 2
• 化学式量合計: 50052.99

構造登録者

Yan, Y.-H.,Li, G.-B. (登録日: 2021-01-23, 公開日: 2022-01-26, 最終更新日: 2023-11-29)

主引用文献

Yan, Y.H.,Li, W.,Chen, W.,Li, C.,Zhu, K.R.,Deng, J.,Dai, Q.Q.,Yang, L.L.,Wang, Z.,Li, G.B.
Structure-guided optimization of 1H-imidazole-2-carboxylic acid derivatives affording potent VIM-Type metallo-beta-lactamase inhibitors.
Eur.J.Med.Chem., 228:113965-113965, 2022

PubMed Abstract: Production of metallo-β-lactamases (MBLs) in bacterial pathogens is an important cause of resistance to the 'last-resort' carbapenem antibiotics. Development of effective MBL inhibitors to reverse carbapenem resistance in Gram-negative bacteria is still needed. We herein report X-ray structure-guided optimization of 1H-imidazole-2-carboxylic acid (ICA) derivatives by considering how to engage with the active-site flexible loops and improve penetration into Gram-negative bacteria. Structure-activity relationship studies revealed the importance of appropriate substituents at ICA 1-position to achieve potent inhibition to class B1 MBLs, particularly the Verona Integron-encoded MBLs (VIMs), mainly by involving ingenious interactions with the flexible active site loops as observed by crystallographic analyses. Of the tested ICA inhibitors, 55 displayed potent synergistic antibacterial activity with meropenem against engineered Escherichia coli strains and even intractable clinically isolated Pseudomonas aeruginosa producing VIM-2 MBL. The morphologic and internal structural changes of bacterial cells after treatment further demonstrated that 55 crossed the outer membrane and reversed the activity of meropenem. Moreover, 55 showed good pharmacokinetic and safety profile in vivo, which could be a potential candidate for combating VIM-mediated Gram-negative carbapenem resistance.

PubMed: 34763944
DOI: 10.1016/j.ejmech.2021.113965

実験手法

X-RAY DIFFRACTION (2.708 Å)