title: Structure activity relationships in PIPC-analogues against Pseudomonas aeruginosa.
abstract: The relationship between the chemical structure and mode of action of piperacillin-analogues (PIPC-analogues) against Pseudomonas aeruginosa was investigated. The antibacterial activities of PIPC-analogues became stronger as the chain length of the alkyl group on the N-4 position in 2,3-dioxopiperazine when tested in constitutively beta-lactamase-producing strain, but not paralleled in wild and beta-lactamase-less strains. The outer membrane permeability was hardly affected by the chain length of the alkyl group at the N-4 position. The stability to beta-lactamase was stronger with the increase of the number of the carbon atoms of N-4 position. In the binding-affinities to the lethal penicillin-binding proteins (PBPs), compounds PIPC (C-2), C-3 and C-4 showed lower ID50 values than compounds C-1, C-6 and C-8. These results suggested that the stability to beta-lactamase was the governing part for the antibacterial activity in constitutively beta-lactamase-producing strain, and the binding affinity to lethal PBPs directly contributed to the antibacterial activity in wild and beta-lactamase-less strains.
authors.affiliation: Research Laboratory, Toyama Chemical Co., Ltd., Japan.
authors.forename: J
authors.initials: J
authors.lastname: Mitsuyama
authors.forename: R
authors.initials: R
authors.lastname: Hori
authors.forename: Y
authors.initials: Y
authors.lastname: Ito
authors.forename: A
authors.initials: A
authors.lastname: Yotsuji
authors.forename: T
authors.initials: T
authors.lastname: Yasuda
authors.forename: I
authors.initials: I
authors.lastname: Saikawa
mesh_terms: D001425:Bacterial Outer Membrane Proteins / Q000032:analysis; D001426:Bacterial Proteins; D002352:Carrier Proteins / Q000378:metabolism; D002463:Cell Membrane Permeability; D004591:Electrophoresis, Polyacrylamide Gel; D006602:Hexosyltransferases; D015394:Molecular Structure; D002267:Muramoylpentapeptide Carboxypeptidase / Q000378:metabolism; D046915:Penicillin-Binding Proteins; D010458:Peptidyl Transferases; D010878:Piperacillin / Q000031:analogs & derivatives* / Q000378:metabolism / Q000494:pharmacology; D011550:Pseudomonas aeruginosa / Q000187:drug effects* / Q000201:enzymology; D001618:beta-Lactamases / Q000096:biosynthesis
chemical_list: D001425:Bacterial Outer Membrane Proteins; D001426:Bacterial Proteins; D002352:Carrier Proteins; D046915:Penicillin-Binding Proteins; D010458:Peptidyl Transferases; D006602:Hexosyltransferases; D002267:Muramoylpentapeptide Carboxypeptidase; D001618:beta-Lactamases; D010878:Piperacillin