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

• Published in: FEMS microbiology letters 1997-12, Vol.157 (1), p.171-175
• Main Authors: Payne, David J., Bateson, John H., Gasson, Brian C., Khushi, Teresa, Proctor, David, Pearson, Stewart C., Reid, Robert
• Format: Article
• Language: English
• Subjects: Bacillus cereus - drug effects; Bacillus cereus - enzymology; beta-Lactamase Inhibitors; beta-Lactamases - chemistry; beta-Lactamases - metabolism; Binding Sites; Esters - chemistry; Esters - metabolism; Esters - pharmacology; Mercaptophenylacetic acid; Metalloenzyme; Metalloproteins - antagonists & inhibitors; Metalloproteins - chemistry; Metalloproteins - metabolism; Substrate Specificity; Sulfhydryl Compounds - chemistry; Sulfhydryl Compounds - metabolism; Sulfhydryl Compounds - pharmacology; Thiolester; Zinc - chemistry; Zinc - metabolism; Zinc - pharmacology; β-Lactamase
• ISSN: 0378-1097; 1574-6968
• DOI: 10.1016/S0378-1097(97)00472-2

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