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 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.
Payne
D J
DJ
SmithKline Beecham Pharmaceuticals, Collegeville, PA 19426-0989, USA. David_J Payne@sbphrd.com
Bateson
J H
JH
Gasson
B C
BC
Khushi
T
T
Proctor
D
D
Pearson
S C
SC
Reid
R
R
D001409:Bacillus cereus / Q000187:drug effects / Q000201:enzymology; D001665:Binding Sites; D004952:Esters / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology*; D008667:Metalloproteins / Q000037:antagonists & inhibitors / Q000737:chemistry / Q000378:metabolism; D013379:Substrate Specificity; D013438:Sulfhydryl Compounds / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology*; D015032:Zinc / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology; D065093:beta-Lactamase Inhibitors; D001618:beta-Lactamases / Q000737:chemistry* / Q000378:metabolism
D004952:Esters; D008667:Metalloproteins; D013438:Sulfhydryl Compounds; D065093:beta-Lactamase Inhibitors; D001618:beta-Lactamases; D015032:Zinc