Binding of monobactams to penicillin-binding proteins of Escherichia coli and Staphylococcus aureus: Relation to antibacterial activity

Abstract

A series of novel monocyclic β-lactam antibiotics having side chains related to penicillin, piperacillin, azlocillin, and cefotaxime were examined with respect to binding to essential penicillin-binding proteins (PBPs) in Escherichia coli and Staphylococcus aureus. In the penicillin series, there was poor binding to all essential PBPs of E. coli (> 100 μg/ml) but good binding to PBPs 1, 2, and 3 of S. aureus (~ 1 μg/ml). In the piperacillin and azlocillin series, there was good binding to PBP 3 of E. coli (0.1 μg/ml) and PBPs 1, 2, and 3 of S. aureus (~ 1 μg/ml). In the cefotaxime series, there was generally good binding to PBP 3 of E. coli (0.1 μg/ml) but poor binding to PBPs 1, 2, and 3 of S. aureus (≥ 100 μg/ml). With a few exceptions in the cefotaxime series, antibacterial activity paralleled essential PBP binding. Binding studies with radioactivity labeled compounds revealed no additional essential monobactam-binding proteins in the two organisms. The studies suggest that monobactams are intrinsically active against both gram-positive and gram-negative bacteria; the activity spectrum of a given monobactam is determined by the binding to essential PBPs, which in turn is determined by the nature of the substituents on the β-lactam nucleus.