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

FEMS Microbiol Lett. 1997 Dec 1;157(1):171-5. doi: 10.1111/j.1574-6968.1997.tb12769.x.


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-beta-lactamases. The inhibition of the Bacteroides fragilis CfiA and Bacillus cereus II metallo-beta-lactamases was Zn2- dependent, greater inhibition being observed at 1 microM ZnSO4 than at 100 microM 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-beta-lactamase with I50 values of between < 1.95 microM and 6 microM and SB-217843 exhibited a similar level of inhibition of this enzyme at 1 and 100 microM Zn2+ (I50 values 5 and 6 microM, respectively). Inhibition of B. cereus II metallo-beta-lactamase by SB-218018 and SB-217782 was competitive with Ki values of 185 microM and 1500 microM, respectively. Therefore, these compounds are specific inhibitors of metallo-beta-lactamases and provide further probes of the active sites of these enzymes.

MeSH terms

  • Bacillus cereus / drug effects
  • Bacillus cereus / enzymology
  • Binding Sites
  • Esters / chemistry
  • Esters / metabolism
  • Esters / pharmacology*
  • Metalloproteins / antagonists & inhibitors
  • Metalloproteins / chemistry
  • Metalloproteins / metabolism
  • Substrate Specificity
  • Sulfhydryl Compounds / chemistry
  • Sulfhydryl Compounds / metabolism
  • Sulfhydryl Compounds / pharmacology*
  • Zinc / chemistry
  • Zinc / metabolism
  • Zinc / pharmacology
  • beta-Lactamase Inhibitors*
  • beta-Lactamases / chemistry*
  • beta-Lactamases / metabolism


  • Esters
  • Metalloproteins
  • Sulfhydryl Compounds
  • beta-Lactamase Inhibitors
  • beta-Lactamases
  • Zinc