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Publication Abstract from PubMed

The emergence and global spread of metallo-beta-lactamase (MBL) mediated resistance to almost all beta-lactam antibacterials poses a serious threat to public health. Since no clinically useful MBL inhibitors have been reported, there is an urgent need to develop new potent broad-spectrum MBL inhibitors effective against antibacterial resistance. Herein, we synthesized a set of 2-substituted ((S)-3-mercapto-2-methylpropanamido) acetic acid derivatives, some of which displayed potent inhibition with high ligand efficiency to the clinically relevant MBL subtypes, Verona Integron-encoded MBL (VIM)-2 and New Delhi MBL (NDM)-1. Kinetic studies revealed that the inhibitors are not strong zinc chelators in solution, and they bind reversibly to VIM-2 but dissociate very slowly. Crystallographic analyses revealed that they inhibit VIM-2 via chelating the active site zinc ions and interacting with catalytically important residues. Further cell- and zebrafish-based assays revealed that the inhibitors slightly increase susceptibility of E. coli cells expressing VIM-2 to meropenem, and they have no apparent toxicity to the viability of HEK293T cells and the zebrafish embryogenesis.

((S)-3-Mercapto-2-methylpropanamido)acetic acid derivatives as metallo-beta-lactamase inhibitors: Synthesis, kinetic and crystallographic studies.,Liu S, Jing L, Yu ZJ, Wu C, Zheng Y, Zhang E, Chen Q, Yu Y, Guo L, Wu Y, Li GB Eur J Med Chem. 2018 Feb 10;145:649-660. doi: 10.1016/j.ejmech.2018.01.032. Epub , 2018 Jan 11. PMID:29353720^[1]

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.