Studies on the mechanism of action of imipenem (N-formimidoylthienamycin) in vitro: Binding to the penicillin-binding proteins (PBPs) in Escherichia coli and Pseudomonas aeruginosa, and inhibition of enzyme activities due to the PBPs in E. coli.

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Abstract
The binding affinities of imipenem (N-formimidoylthienamycin) to penicillin-binding proteins (PBp) of E. coli and P. aeruginosa were determined by 2 methods in which competition with [14C]benzylpenicillin for the binding sites was measured. By both methods imipenem was shown to have very high binding affinities to PBP-2 and -4 in E. coli and P. aeruginosa and appreciable affinities to most of their other major PBP. Higher concentrations of imipenem were required for binding to the PBP-3 in these bacteria. More direct information about the antibacterial activity of imipenem was obtained by measuring its inhibition of the peptidoglycan-synthetic enzyme activities of E. coli PBP. The results of enzyme inhibitions were compatible with those obtained in binding experiments. The antibiotic inhibited the transpeptidase activities of PBP-IA, -1B and -2 and the D-alanine carboxypeptidase activities of PBP-4 and -5. The antibiotic also seemed to cause strong inhibition of the transglycosylase activity of PBP-1A by some unknown mechanism. It inhibited the transpeptidase activity of PBP-3 only weakly, which is consistent with the findings that it had low binding affinity of PBP-3 and did not inhibit septum formation by the cells.

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