New cephamycin antibiotic, CS-1170: binding affinity to penicillin-binding proteins and inhibition of peptidoglycan cross-linking reactions in Escherichia coli

Abstract

The binding activity of CS-1170, a new cephamycin antibiotic, to penicillin-binding proteins (PBPs) in Escherichia coli and Proteus species and the potency of this antibiotic in vitro to inhibit enzymes involved in peptidoglycan cross-linking in E. coli were tested. Similar experiments were carried out with the 7alpha-H analog of CS-1170, R-45656, and the results were compared with those obtained with CS-1170. CS-1170 showed high affinities (compared with that of penicillin G) for E. coli PBP-1A, -1Bs, and -3, the PBPs of higher molecular weight, but not PBP-2. It also inhibited the in vitro peptidoglycan cross linking reaction and concomitant release of d-alanine at very low concentrations (approximately its minimal inhibitory concentration). This antibiotic also showed very high affinity for PBP-4, -5, and -6, the PBPs of lower molecular weight, and at extremely low concentrations it inhibited d-alanine carboxypeptidases IA and IB, corresponding to PBP-5/6 and PBP-4, respectively. CS-1170 seemed to be resistant to the beta-lactamase activity of PBP-5 and -6 in E. coli and Proteus species. R-45656 showed as high an affinity for PBP-1A, -1Bs, and -3 as CS-1170, but unlike CS-1170, it had low affinities for PBP-4, -5, and -6. The concentrations of R-45656 required for inhibition of d-alanine carboxypeptidases IA and IB were also much higher than those of CS-1170. R-45656 showed rather low activities in inhibiting the in vitro cross-linking reaction of peptidoglycan and concomitant release of d-alanine. Synergism was observed in 9 of 22 strains examined between CS-1170 and mecillinam, which bound specifically to PBP-2.