Interaction of the novel penem CGP 31 608 and its enantiomer with type Id beta-lactamase and penicillin-binding proteins.
The novel penem CGP 31,608 (5R, 6S, 8R) and its enantiomer CGP 32,879 (5S, 6R, 8S) were shown to be essentially stable against hydrolysis by type Id beta-lactamase isolated from Pseudomonas aeruginosa 18S/H. CGP 31 608 was a potent progressive inhibitor of this enzyme (150 = 32 microM), which was only weakly inhibited by CGP 32,879 (150 = 460 microM). CGP 31,608 had the highest affinity for penicillin-binding protein (PBP) 4 from Escherichia coli K-12 (150 = 1 microgram/ml), followed by PBPs 2 (10 micrograms/ml) and 1A/1Bs (100 micrograms/ml); CGP 32,879 did not inhibit binding of 14C-benzylpenicillin to the PBPs. The steric configuration of the beta-lactam nucleus of penems appears to strongly influence their affinity for beta-lactamases and target PBPs. The balanced spectrum of CGP 31,608 may be explained by its beta-lactamase stability and affinity for several vital PBPs.
D000900:Anti-Bacterial Agents / Q000378:metabolism* / Q000494:pharmacology; D001426:Bacterial Proteins; D002352:Carrier Proteins / Q000378:metabolism*; D004790:Enzyme Induction / Q000187:drug effects; D006602:Hexosyltransferases; D006868:Hydrolysis; D007769:Lactams; D002267:Muramoylpentapeptide Carboxypeptidase / Q000378:metabolism*; D046915:Penicillin-Binding Proteins; D010458:Peptidyl Transferases; D011550:Pseudomonas aeruginosa / Q000187:drug effects / Q000201:enzymology; D065093:beta-Lactamase Inhibitors; D001618:beta-Lactamases / Q000096:biosynthesis / Q000378:metabolism*; D047090:beta-Lactams
D000900:Anti-Bacterial Agents; D001426:Bacterial Proteins; D002352:Carrier Proteins; D007769:Lactams; D046915:Penicillin-Binding Proteins; D065093:beta-Lactamase Inhibitors; D047090:beta-Lactams; C052019:CGP 31608; D010458:Peptidyl Transferases; D006602:Hexosyltransferases; D002267:Muramoylpentapeptide Carboxypeptidase; D001618:beta-Lactamases