6JN6

Metallo-Beta-Lactamase VIM-2 in complex with Dual MBL/SBL Inhibitor MS19

6JN6 の概要

• エントリーDOI: 10.2210/pdb6jn6/pdb
• 分子名称: Beta-lactamase class B VIM-2, ZINC ION, [(1S)-2-(1-benzofuran-3-yl)-1-[[(2S)-2-methyl-3-sulfanyl-propanoyl]amino]ethyl]boronic acid, ... (5 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: 50641.83

構造登録者

Li, G.-B.,Liu, S. (登録日: 2019-03-13, 公開日: 2019-07-17, 最終更新日: 2023-11-22)

主引用文献

Wang, Y.L.,Liu, S.,Yu, Z.J.,Lei, Y.,Huang, M.Y.,Yan, Y.H.,Ma, Q.,Zheng, Y.,Deng, H.,Sun, Y.,Wu, C.,Yu, Y.,Chen, Q.,Wang, Z.,Wu, Y.,Li, G.B.
Structure-Based Development of (1-(3'-Mercaptopropanamido)methyl)boronic Acid Derived Broad-Spectrum, Dual-Action Inhibitors of Metallo- and Serine-beta-lactamases.
J.Med.Chem., 62:7160-7184, 2019

PubMed Abstract: The emergence and spread of bacterial pathogens acquired metallo-β-lactamase (MBL) and serine-β-lactamase (SBL) medicated β-lactam resistance gives rise to an urgent need for the development of new dual-action MBL/SBL inhibitors. Application of a pharmacophore fusion strategy led to the identification of (2')-(1-(3'-mercapto-2'-methylpropanamido)methyl)boronic acid () as a new dual-action inhibitor, which manifests broad-spectrum inhibition to representative MBL/SBL enzymes, including the widespread VIM-2 and KPC-2. Guided by the VIM-2: and KPC-2: complex structures, further structural optimization yielded new, more potent dual-action inhibitors. Selectivity studies indicated that the inhibitors had no apparent inhibition to human angiotensin-converting enzyme-2 and showed selectivity across serine hydrolyases in and human HEK293T cells labeled by the activity-based probe TAMRA-FP. Moreover, the inhibitors displayed potentiation of meropenem efficacy against MBL- or SBL-positive clinical isolates without apparent cytotoxicity. This work will aid efforts to develop new types of clinically useful dual-action inhibitors targeting MBL/SBL enzymes.

PubMed: 31269398
DOI: 10.1021/acs.jmedchem.9b00735

実験手法

X-RAY DIFFRACTION (1.602 Å)