5mm9 | pdb_00005mm9

VIM-2_2b. Metallo-beta-Lactamase Inhibitors by Bioisosteric Replacement: Preparation, Activity and Binding

spinqualitylabelsall models 5mm9, resolution 1.55Å Show:Asymmetric Unit Biological Assembly Drag the structure with the mouse to rotate   Export Animated Image   Print3D Structural highlights 5mm9 is a 2 chain structure with sequence from "bacillus_aeruginosus"_(schroeter_1872)_trevisan_1885 "bacillus aeruginosus" (schroeter 1872) trevisan 1885. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance. Ligands: 8SH, MG, ZN Gene: blaVIM-17 ("Bacillus aeruginosus" (Schroeter 1872) Trevisan 1885) Resources: FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT Publication Abstract from PubMed Bacterial resistance is compromising the use of beta-lactam antibiotics including carbapenems. The main resistance mechanism against beta-lactams is hydrolysis of the beta-lactam ring mediated by serine- or metallo-beta-lactamases (MBLs). Although several inhibitors of MBLs have been reported, none has been developed into a clinically useful inhibitor. Mercaptocarboxylic acids are among the most prominent scaffolds reported as MBL inhibitors. In this study, the carboxylate group of mercaptocarboxylic acids was replaced with bioisosteric groups like phosphonate esters, phosphonic acids and NH-tetrazoles. The influence of the replacement on the bioactivity and inhibitor binding was evaluated. A series of bioisosteres of previously reported inhibitors was synthesized and evaluated against the MBLs VIM-2, NDM-1 and GIM-1. The most active inhibitors combined a mercapto group and a phosphonate ester or acid, with two/three carbon chains connecting a phenyl group. Surprisingly, also compounds containing thioacetate groups instead of thiols showed low IC50 values. High-resolution crystal structures of three inhibitors in complex with VIM-2 revealed hydrophobic interactions for the diethyl groups in the phosphonate ester (inhibitor 2b), the mercapto bridging the two active site zinc ions, and tight stacking of the benzene ring to the inhibitor between Phe62, Tyr67, Arg228 and His263. The inhibitors show reduced enzyme activity in Escherichia coli cells harboring MBL. The obtained results will be useful for further structural guided design of MBL inhibitors. Metallo-beta-lactamase inhibitors by bioisosteric replacement: Preparation, activity and binding.,Skagseth S, Akhter S, Paulsen MH, Muhammad Z, Lauksund S, Samuelsen O, Leiros HS, Bayer A Eur J Med Chem. 2017 Apr 14;135:159-173. doi: 10.1016/j.ejmech.2017.04.035. PMID:28445786 From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. See Also Beta-lactamase 3D structures

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