Inhibition of metallo-β-lactamases by a series of thiol ester derivatives of mercaptophenylacetic acid

Abstract

A series of mercaptophenylacetic acid thiol esters bearing a phenyl substituent adjacent to the carboxylic acid function has been shown to be inhibitors of metallo-β-lactamases. The inhibition of the Bacteroides fragilis CfiA and Bacillus cereus II metallo-β-lactamases was Zn 2+ dependent, greater inhibition being observed at 1 μM ZnSO 4 than at 100 μM ZnSO 4. Despite this Zn 2+ dependency, isothermal titration calorimetry studies illustrated that representative compounds had no detectable affinity for Zn 2+ ( K>1 mM). This indicates that their mode of inhibition was not by chelation of the active site Zn 2+. Greatest potency was observed against the Stenotrophomonas maltophilia L1 metallo-β-lactamase with I 50 values of between <1.95 μM and 6 μM and SB-217843 exhibited a similar level of inhibition of this enzyme at 1 and 100 μM Zn 2+ (I 50 values 5 and 6 μM, respectively). Inhibition of B. cereus II metallo-β-lactamase by SB-218018 and SB-217782 was competitive with K i values of 185 μM and 1500 μM, respectively. Therefore, these compounds are specific inhibitors of metallo-β-lactamases and provide further probes of the active sites of these enzymes.