Discovery of [1,2,4]Triazole Derivatives as New Metallo-?-Lactamase Inhibitors.

ABSTRACT: The emergence and spread of metallo-?-lactamase (MBL)-mediated resistance to ?-lactam antibacterials has already threatened the global public health. A clinically useful MBL inhibitor that can reverse ?-lactam resistance has not been established yet. We here report a series of [1,2,4]triazole derivatives and analogs, which displayed inhibition to the clinically relevant subclass B1 (Verona integron-encoded MBL-2) VIM-2. 3-(4-Bromophenyl)-6,7-dihydro-5H-[1,2,4]triazolo [3,4-b][1,3]thiazine (5l) manifested the most potent inhibition with an IC50 (half-maximal inhibitory concentration) value of 38.36 ?M. Investigations of 5l against other B1 MBLs and the serine ?-lactamases (SBLs) revealed the selectivity to VIM-2. Molecular docking analyses suggested that 5l bound to the VIM-2 active site via the triazole involving zinc coordination and made hydrophobic interactions with the residues Phe61 and Tyr67 on the flexible L1 loop. This work provided new triazole-based MBL inhibitors and may aid efforts to develop new types of inhibitors combating MBL-mediated resistance.

SUBMITTER: Yuan C 

PROVIDER: S-EPMC6982996 | biostudies-literature | 2019 Dec

REPOSITORIES: biostudies-literature