title: Target affinities of faropenem to and its impact on the morphology of gram-positive and gram-negative bacteria.
abstract: Faropenem is a new oral beta-lactam antibiotic unique from carbapenems and other available beta-lactams. Determinants of the in vitro activity of beta-lactam antibiotics include affinity to penicillin-binding proteins (PBPs) and beta-lactamase stability. In this study, the binding affinity of faropenem to various PBPs and its impact on the morphology of Staphylococcus aureus and Escherichia coli were evaluated. In general, faropenem demonstrated high binding affinity to high-molecular-weight PBPs but low affinity to low-molecular-weight PBPs. In S. aureus and Streptococcus pneumoniae, faropenem exhibited high binding affinity to PBP1, followed by PBP3 and PBP2. In E. coli, faropenem showed the highest affinity for PBP2, followed by PBP1A, PBP1B, PBP3 and PBP4. In Proteus vulgaris, binding was highest to PBP4, followed by PBP1A, PBP2 and PBP3. In Serratia marcescens, faropenem bound preferentially to PBP2 and PBP4. Exposure of S. aureus to faropenem at minimum inhibitory concentrations (MICs) of 1/8 or 1/4 resulted in irregular septum formation. At 1x MIC or higher, a larger number of lysed cells were observed. Exposure of E. coli to 1/8x MIC or 1/4x MIC also induced changes in cellular shape; the normal rod-shaped form changed to a spherical form in a time-dependent manner. After exposure of E. coli to 1x MIC for 2 h, bulging-shaped E. coli cells were observed and after 4 h of exposure cell lysis was demonstrated. In the presence of 4x MIC, spheroplast-like forms and cell lysis were observed. The morphological changes triggered by faropenem are in agreement with the PBP binding affinities reported. Thus, the high binding affinities of faropenem to PBPs from gram-negative and gram-positive bacteria are mirrored by its pronounced and concentration-dependent bactericidal effect.
authors.affiliation: Pharma Research Center, Bayer AG, Wuppertal, Germany. axel.dalhoff.ad@bayer-ag.de
authors.forename: A
authors.initials: A
authors.lastname: Dalhoff
authors.forename: T
authors.initials: T
authors.lastname: Nasu
authors.forename: K
authors.initials: K
authors.lastname: Okamoto
mesh_terms: D000900:Anti-Bacterial Agents / Q000378:metabolism / Q000494:pharmacology*; D001426:Bacterial Proteins / Q000037:antagonists & inhibitors; D001665:Binding Sites; D002352:Carrier Proteins / Q000037:antagonists & inhibitors; D002444:Cefuroxime / Q000378:metabolism / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D004755:Enterobacteriaceae / Q000187:drug effects* / Q000378:metabolism / Q000648:ultrastructure; D004795:Enzyme Stability; D029968:Escherichia coli Proteins; D006095:Gram-Positive Cocci / Q000187:drug effects* / Q000378:metabolism / Q000648:ultrastructure; D006602:Hexosyltransferases / Q000037:antagonists & inhibitors; D015378:Imipenem / Q000378:metabolism / Q000494:pharmacology; D066298:In Vitro Techniques; D007769:Lactams; D008855:Microscopy, Electron, Scanning; D002267:Muramoylpentapeptide Carboxypeptidase / Q000037:antagonists & inhibitors; D046915:Penicillin-Binding Proteins; D046928:Peptidoglycan Glycosyltransferase; D010458:Peptidyl Transferases / Q000037:antagonists & inhibitors; D046929:Serine-Type D-Ala-D-Ala Carboxypeptidase; D001618:beta-Lactamases / Q000378:metabolism*; D047090:beta-Lactams
chemical_list: D000900:Anti-Bacterial Agents; D001426:Bacterial Proteins; D002352:Carrier Proteins; D029968:Escherichia coli Proteins; D007769:Lactams; D046915:Penicillin-Binding Proteins; D047090:beta-Lactams; D015378:Imipenem; D010458:Peptidyl Transferases; D006602:Hexosyltransferases; D046928:Peptidoglycan Glycosyltransferase; C478681:penicillin-binding protein 1B, E coli; D046929:Serine-Type D-Ala-D-Ala Carboxypeptidase; D002267:Muramoylpentapeptide Carboxypeptidase; D001618:beta-Lactamases; C107057:fropenem; D002444:Cefuroxime