Antibacterial activity and penicillin-binding protein affinity of new cephalosporin derivatives in Staphylococcus aureus and Escherichia coli.

A series of C3-substituted cephalosporins with different levels of oxidation was synthesized and the activities of eight compounds, including affinity for penicillin-binding proteins (PBPs), in Staphylococcus aureus and Escherichia coli were studied. The more hydrophobic cephalosporins, with a thiophene moiety at the C7 position, were more active than C7-methoxyiminoaminothiazole derivatives against S. aureus H (beta-lactam-susceptible), and compounds with a thioether function at C3 were more active than those with a sulphonyl function at this position. In contrast, the most active compounds against E. coli were hydrophilic, zwitterionic C7-methoxyimino-aminothiazole C3-thioether cephalosporins. The physicochemical properties of the most active compounds were in accord with those predicted for rapid outer membrane penetration. However, among the thiophene cephalosporins the dianionic sulphonyl compounds were more active than the monoanionic thioether derivatives. There was a reasonably good correlation between MICs and PBP affinities for S. aureus H. The compounds had most affinity for PBP 1 and least for PBP 4. The two most potent compounds had high affinities for PBPs 1, 2 and 3. The compounds had low affinities for the beta-lactam-insensitive PBP 2a of methicillin-resistant S. aureus strain DU4916-K7. The novel cephalosporins had the highest affinities for PBPs 1a/1b and 3 of E. coli DCO. The major morphological response of E. coli to the compounds was cell elongation.