Abstract
The emergence and spread of metallo-β-lactamase (MBL)-mediated resistance to β-lactam antibacterials has already threatened the global public health. A clinically useful MBL inhibitor that can reverse β-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 μM. Investigations of 5l against other B1 MBLs and the serine β-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.
Highlights
The β-lactams are the most widely used antibacterial agents in clinical practice for many years [1]
These results suggest that 5l is a selective Verona integron-encoded MBLs (VIMs)-2 MBL inhibitor
The preliminary SAR analyses on these synthesized derivatives led to the identification of a number of VIM-2 inhibitors, e.g., 5l
Summary
The β-lactams are the most widely used antibacterial agents in clinical practice for many years [1]. One of the important mechanisms of resistance to β-lactam antibiotics is the production of β-lactamases that can hydrolyze the core β-lactam ring by a nucleophilic reaction to inactive the drugs [6,7]. According to the catalytic mechanisms, β-lactamases are grouped into two catalogs: serine β-lactamases (SBLs, using the active site serine residue as a nucleophile) and metallo-β-lactamases To circumvent bacterial resistance mediated by β-lactamases, five clinically useful SBL inhibitors have been developed, including clavulanic acid, sulbactam, tazobactam, avibactam, and vaborbactam [9,10,11,12]. There remain no FDA-approved small-molecule inhibitors for MBLs, which can hydrolyze almost all β-lactam antibiotics, including the last-generation cephalosporins and carbapenems [13,14]. B1 MBLs are the most clinically relevant, typically including
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