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 Zn2+ dependent, greater inhibition being observed at 1 μM ZnSO4 than at 100 μM ZnSO4. Despite this Zn2+ dependency, isothermal titration calorimetry studies illustrated that representative compounds had no detectable affinity for Zn2+ (K>1 mM). This indicates that their mode of inhibition was not by chelation of the active site Zn2+. Greatest potency was observed against the Stenotrophomonas maltophilia L1 metallo-β-lactamase with I50 values of between