title: 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 beta-lactamase and binding affinity to penicillin-binding proteins.
abstract: The relationship between the chemical structure and the mode of action of piperacillin-analogues (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 beta-lactamase and binding affinity to penicillin-binding proteins (PBPs). The outer membrane permeability and stability to beta-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.
authors.forename: J
authors.initials: J
authors.lastname: Mitsuyama
authors.forename: M
authors.initials: M
authors.lastname: Takahata
authors.forename: T
authors.initials: T
authors.lastname: Yasuda
authors.forename: I
authors.initials: I
authors.lastname: Saikawa
mesh_terms: D001426:Bacterial Proteins; D001667:Binding, Competitive; D002352:Carrier Proteins / Q000378:metabolism*; D002463:Cell Membrane Permeability; D055598:Chemical Phenomena; D002621:Chemistry; D004926:Escherichia coli / Q000187:drug effects; D006602:Hexosyltransferases; D007711:Klebsiella pneumoniae / Q000187:drug effects; D002267:Muramoylpentapeptide Carboxypeptidase / Q000378:metabolism*; D010400:Penicillin G / Q000378:metabolism; D046915:Penicillin-Binding Proteins; D010458:Peptidyl Transferases; D010878:Piperacillin / Q000031:analogs & derivatives* / Q000378:metabolism / Q000494:pharmacology; D013329:Structure-Activity Relationship; D001618:beta-Lactamases / Q000378:metabolism*
chemical_list: D001426:Bacterial Proteins; D002352:Carrier Proteins; D046915:Penicillin-Binding Proteins; D010458:Peptidyl Transferases; D006602:Hexosyltransferases; D002267:Muramoylpentapeptide Carboxypeptidase; D001618:beta-Lactamases; D010400:Penicillin G; D010878:Piperacillin