7CJL

Metallo-Beta-Lactamase VIM-2 in complex with (S)-N-(3-(2H-tetrazol-5-yl)phenyl)-3-mercapto-2-methylpropanamide

Summary for 7CJL

• Entry DOI: 10.2210/pdb7cjl/pdb
• Descriptor: Beta-lactamase class B VIM-2, ZINC ION, FORMIC ACID, ... (5 entities in total)
• Functional Keywords: metallo-beta-lactamase vim-2, vim-2, hydrolase
• Biological source: Pseudomonas aeruginosa
• Total number of polymer chains: 2
• Total formula weight: 50193.18

Authors

Yan, Y.-H.,Chen, J.,Zhan, Z.,Yu, Z.-J.,Li, G.,Li, G.-B.,Guo, L.,Wu, Y. (deposition date: 2020-07-11, release date: 2021-07-14, Last modification date: 2023-11-29)

Primary citation

Yan, Y.H.,Chen, J.,Zhan, Z.,Yu, Z.J.,Li, G.,Guo, L.,Li, G.B.,Wu, Y.,Zheng, Y.
Discovery of mercaptopropanamide-substituted aryl tetrazoles as new broad-spectrum metallo-beta-lactamase inhibitors.
Rsc Adv, 10:31377-31384, 2020

PubMed Abstract: β-Lactam antibiotic resistance mediated by metallo-β-lactamases (MBL) has threatened global public health. There are currently no available inhibitors of MBLs for clinical use. We previously reported the ruthenium-catalyzed meta-selective C-H nitration synthesis method, leading to some -mercaptopropanamide substituted aryl tetrazoles as new potent MBL inhibitors. Here, we described the structure-activity relationship of - and -mercaptopropanamide substituted aryl tetrazoles with clinically relevant MBLs. The resulting most potent compound 13a showed IC values of 0.044 μM, 0.396 μM and 0.71 μM against VIM-2, NDM-1 and IMP-1 MBL, respectively. Crystallographic analysis revealed that 13a chelated to active site zinc ions the thiol group and interacted with the catalytically important residues Asn233 and Tyr67, providing further structural information for the development of thiol based MBL inhibitors.

PubMed: 35520685
DOI: 10.1039/d0ra06405j

Experimental method

X-RAY DIFFRACTION (1.789 Å)