Open AccessInhibition of metallo‐β‐lactamases by a series of thiol ester derivatives of mercaptophenylacetic acid
Author(s) -
Payne David J.,
Bateson John H.,
Gasson Brian C.,
Khushi Teresa,
Proctor David,
Pearson Stewart C.,
Reid Robert
Publication year - 1997
Publication title -
fems microbiology letters
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.899
H-Index - 151
eISSN - 1574-6968
pISSN - 0378-1097
DOI - 10.1111/j.1574-6968.1997.tb12769.x
Subject(s) - isothermal titration calorimetry , bacillus cereus , thiol , stereochemistry , chemistry , enzyme , active site , non competitive inhibition , stenotrophomonas maltophilia , enzyme inhibitor , chelation , biochemistry , biology , organic chemistry , bacteria , genetics , pseudomonas aeruginosa
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.