title: Diffusion of meropenem and imipenem through the outer membrane of Escherichia coli K-12 and correlation with their antibacterial activities.
abstract: The outer membrane permeability to meropenem and imipenem in Escherichia coli K-12 was investigated, and its porin-deficient mutants were transformed with a constructed vector carrying the carbapenem-hydrolyzing CphA metallo-beta-lactamase gene. By using the method of Zimmermann and Rosselet, meropenem was shown to penetrate through the outer membrane of E. coli K-12 five times faster than cephaloridine but twice as slowly as imipenem. Lack of one or both porins significantly reduced the penetration of both carbapenems. No evidence of specific porin pathways of the type described in Pseudomonas aeruginosa was found. Despite its slower penetration, meropenem was two to eight times more active than imipenem against both parent and porin-defective mutants, whether harbouring CphA beta-lactamase or not. Meropenem was also more active than imipenem against E. coli DC2, a strain with a breakdown in the outer membrane permeability which made periplasmic concentrations of beta-lactams similar to the external concentrations. In this strain, meropenem caused a more than 50% reduction in cell number increase at a concentration very close to the 50% inhibitory concentration for penicillin-binding protein type 2 (PBP 2), whereas imipenem, at the same concentration, did not significantly inhibit cell growth. This result was explained by the higher affinity of meropenem for PBP 3 compared with imipenem and supports the conclusion that synergistic inhibition of both PBPs was the main mechanism in the better antibacterial activity of meropenem.
authors.affiliation: Istituto di Microbiologia, Università degli Studi di Verona, Italy.
authors.forename: G
authors.initials: G
authors.lastname: Cornaglia
authors.forename: L
authors.initials: L
authors.lastname: Guan
authors.forename: R
authors.initials: R
authors.lastname: Fontana
authors.forename: G
authors.initials: G
authors.lastname: Satta
mesh_terms: D001419:Bacteria / Q000187:drug effects* / Q000235:genetics; D001425:Bacterial Outer Membrane Proteins / Q000737:chemistry*; D001426:Bacterial Proteins; D002352:Carrier Proteins; D003470:Culture Media; D004058:Diffusion; D004591:Electrophoresis, Polyacrylamide Gel; D004926:Escherichia coli / Q000187:drug effects*; D006602:Hexosyltransferases; D015378:Imipenem / Q000737:chemistry* / Q000494:pharmacology; D007700:Kinetics; D000077731:Meropenem; D008826:Microbial Sensitivity Tests; D002267:Muramoylpentapeptide Carboxypeptidase; D046915:Penicillin-Binding Proteins; D010458:Peptidyl Transferases; D010539:Permeability; D010957:Plasmids; D013845:Thienamycins / Q000737:chemistry* / Q000494:pharmacology; D014170:Transformation, Genetic; D001618:beta-Lactamases / Q000378:metabolism
chemical_list: D001425:Bacterial Outer Membrane Proteins; D001426:Bacterial Proteins; D002352:Carrier Proteins; D003470:Culture Media; D046915:Penicillin-Binding Proteins; D013845:Thienamycins; D015378:Imipenem; D010458:Peptidyl Transferases; D006602:Hexosyltransferases; D002267:Muramoylpentapeptide Carboxypeptidase; D001618:beta-Lactamases; D000077731:Meropenem