Design, synthesis, and in vitro and biological evaluation of potent amino acid-derived thiol inhibitors of the metallo-β-lactamase IMP-1

There are currently no clinically available inhibitors of metallo-β-lactamases (MBLs). These enzymes confer resistance to bacteria against a broad range of commonly used β-lactam antibiotics, and are produced by an increasing number of bacterial pathogens. In this study, several thiol derivatives of l-amino acids were designed and synthesized, and their inhibitory effects against the metallo-β-lactamase IMP-1 (subclass B1) were investigated. The most potent compound, derived from l-tyrosine, exhibited competitive inhibition, with a K_i of 86 nM. The ability of this compound to render MBL-expressing bacteria susceptible to imipenem was examined. Reductions in MIC values up to 5.2 - fold were observed.