Interaction of the novel penem CGP 31 608 and its enantiomer with type Id beta-lactamase and penicillin-binding proteins.

Abstract

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.