New Antipseudomonal Penicillin, PC-904: Affinity to Penicillin-Binding Proteins and Inhibition of the Enzyme Cross-Linking Peptidoglycan

The mechanism of action of a new antipseudomonal penicillin, PC-904, was studied with respect to its binding affinities to penicillin-binding proteins (PBPs) and its inhibitory activities on cross-linking enzymes of peptidoglycan synthesis in vitro. PC-904 showed especially high affinity (compared with that of penicillin G) toEscherichia coli PBP-3. It also had high affinities to PBP-2 and -1Bs and low affinities to PBP-1A, -4, -5, and -6. Similar results were obtained withPseudomonas aeruginosa , in which this antibiotic showed very high affinity (compared with that of penicillin G) to PBP-3, -1A (presumably corresponding toE. coli PBP-1Bs), and -2; there was especially high affinity to PBP-3 and much less affinity to PBP-1B (presumably corresponding toE. coli PBP-1A). These results are compatible with morphological observations that at concentrations near its minimal inhibitory concentration or less, this antibiotic induced the formation of filamentous cells ofE. coli andP. aeruginosa . At higher concentrations or after prolonged incubation, it induced lysis of the cells. The remarkably high affinity of PC-904 to pseudomonal PBP-3, -1A, and -2 may partly explain the potent antipseudomonal activity of this antibiotic. InE. coli , the concentration of PC-904 required to inhibit the cross-linking reaction in enzymatic peptidoglycan synthesis, presumably carried out by PBP-1Bs, was as low as the inhibitory concentrations of penicillin G, ampicillin, and carbenicillin.