THE MECHANISM OF ACTION OF PIPERACILLIN-ANALOGUES IN VITRO; EFFECT OF THE CARBON NUMBER AT THE N-4 POSITION OF 2, 3-DIOXOPIPERAZINE ON THE OUTER MEMBRANE PERMEABILITY, STABILITY TO β-LACTAMASE AND BINDING AFFINITY TO PENICILLIN-BINDING PROTEINS

Abstract

The relationship between the chemical structure and the mode of action of piperacillinanalogues (PIPC-analogues) against Escherichia coli and Klebsiella pneumoniae were investigated. The antibacterial activity of PIPC-analogues increased with an increase in the number of carbon atoms at the N-4 position of 2, 3-dioxopiperazine. Their mode of action is discussed on the basis of the results of studies on outer membrane permeability, stability to β-lactamase and binding affinity to penicillin-binding proteins (PBPs). The outer membrane permeability and stability to β-lactamase were hardly affected by the chain length of the alkyl group at the N-4 position. On the other hand, the affinity to PBPs, especially to PBP 3, became stronger with increase of the number of carbon atoms at N-4 position. These results suggest that increased affinity to PBPs is the main reason for the increased antibacterial activity of the PIPC-analogues reported here.