Use of novel boronic acid transition state inhibitors to probe substrate affinity in SHV-type extended-spectrum beta-lactamases.
Boronic acid transition state inhibitors (BATSIs) with R1 side chains of cefotaxime and ceftazidime were assayed against SHV-1, SHV-2, SHV-5, D104K, and D104K G238S beta-lactamases. The D104K variant was the most susceptible to inhibition by the ceftazidime BATSI (Ki, 730+/-80 nM), while the D104K G238S variant was the most susceptible to the cefotaxime BATSI (Ki, 1.1+/-0.2 microM).
Thomson
Jodi M
JM
Department of Pharmacology, Case Western Reserve University School of Medicine, and Research Service, Louis Stokes Cleveland Veterans Affairs Medical Center, 10701 East Blvd., Cleveland, OH 44106, USA.
Prati
Fabio
F
Bethel
Christopher R
CR
Bonomo
Robert A
RA
D000900:Anti-Bacterial Agents / Q000494:pharmacology*; D001897:Boronic Acids / Q000494:pharmacology*; D002442:Ceftazidime / Q000494:pharmacology; D015195:Drug Design; D004791:Enzyme Inhibitors / Q000138:chemical synthesis / Q000737:chemistry*; D013379:Substrate Specificity; D065093:beta-Lactamase Inhibitors; D001618:beta-Lactamases / Q000187:drug effects / Q000378:metabolism
D000900:Anti-Bacterial Agents; D001897:Boronic Acids; D004791:Enzyme Inhibitors; D065093:beta-Lactamase Inhibitors; D002442:Ceftazidime; D001618:beta-Lactamases