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.