INHIBITION OF METALLO-BETA-LACTAMASES BY A SERIES OF THIOL ESTER DERIVATIVES OF MERCAPTOPHENYLACETIC ACID

A series of mercaptophenylacetic acid thiol esters bearing a phenyl su bstituent adjacent to the carboxylic acid function has been shown to b e inhibitors of metallo-beta-lactamases. The inhibition of the Bactero ides fragilis CfiA and Bacillus cereus II metallo-beta-lactamases was Zn2+ dependent, greater inhibition being observed at 1 mu M ZnSO4 than at 100 mu M 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 mod e of inhibition was not by chelation of the active site Zn2+. Greatest potency was observed against the Stenotrophomonas maltophilia L1 meta llo-beta-lactamase with I-50 values of between < 1.95 mu M and 6 mu M and SB-217843 exhibited a similar level of inhibition of this enzyme a t 1 and 100 mu M Zn2+ (I-50 values 5 and 6 mu M, respectively). Inhibi tion of B. cereus II metallo-beta-lactamase by SB-218018 and SB-217782 was competitive with K-i values of 185 mu M and 1500 mu M, respective ly. Therefore, these compounds are specific inhibitors of metallo-beta -lactamase and provide further probes of the active sites of these enz ymes.