Optimization of amino acid thioesters as inhibitors of metallo-β-lactamase L1

The emergence of antibiotic resistance caused by metallo-beta-lactamases (MbLs) is a global public health problem. Recently, we found amino acid thioesters to be a highly promising scaffold for inhibitors of the M beta L L1. In order to optimize this series of inhibitors, nine new amino acid thioesters were developed by modifying the substituents on the N-terminus of the thioesters and the groups representing the amino acid side chain. Biological activity assays indicate that all of them are very potent inhibitors of L1 with an IC50 value range of 20-600 nM, lower than those of most of the previously reported inhibitors of this scaffold. Analysis of structure-activity relationship reveals that big hydrophobic substituents on the N-terminus and a methionine amino acid side chain improves inhibitory activity of the thioesters. All these inhibitors are able to restore antibacterial activity of a beta-lactam antibiotic against Escherichia coli BL21(DE3) cells producing L1 to that against E. coli cells lacking a beta-lactamase. Docking studies reveal that a large N-terminal hydrophobic group results in a slightly different binding mode than smaller hydrophobic groups at the same position. (C) 2016 Elsevier Ltd. All rights reserved.