title: The binding of antibiotics in OmpF porin.
abstract: The structure of OmpF porin in complex with three common antibiotics (zwitterionic ampicillin, anionic ertapenem, and di-anionic carbenicillin) was determined using X-ray crystallography. The three antibiotics are found to bind within the extracellular and periplasmic pore vestibules, away from the narrow OmpF constriction zone. Using the X-ray structures as a starting point, nonequilibrium molecular dynamics simulations with an applied membrane voltage show that ionic current through the OmpF channel is blocked with bound ampicillin, but not with bound carbenicillin. The susceptibility of Escherichia coli expressing OmpF mutants to ampicillin and carbenicillin was also experimentally characterized using microbiologic assays. These results show that general diffusion by OmpF porins allows for transfer of molecules with varied charged states and give insights into the design of more efficient antibiotics. A better understanding of this mechanism will shed light on nature's way of devising channels able to enhance the transport of molecules through membranes.
authors.affiliation: Department of Biochemistry and Molecular Biology, Gordon Center for Integrative Science, The University of Chicago, 929 East 57(th) Street, Chicago, IL 60637, USA.
authors.forename: Brigitte K
authors.initials: BK
authors.lastname: Ziervogel
authors.affiliation: Department of Biochemistry and Molecular Biology, Gordon Center for Integrative Science, The University of Chicago, 929 East 57(th) Street, Chicago, IL 60637, USA. Electronic address: roux@uchicago.edu.
authors.forename: Benoît
authors.initials: B
authors.lastname: Roux
mesh_terms: D000595:Amino Acid Sequence; D000667:Ampicillin / Q000737:chemistry* / Q000378:metabolism / Q000494:pharmacology; D000900:Anti-Bacterial Agents / Q000737:chemistry* / Q000378:metabolism / Q000494:pharmacology; D001665:Binding Sites; D002228:Carbenicillin / Q000737:chemistry* / Q000378:metabolism / Q000494:pharmacology; D018360:Crystallography, X-Ray; D004058:Diffusion; D052978:Disk Diffusion Antimicrobial Tests; D000077727:Ertapenem; D004926:Escherichia coli / Q000187:drug effects / Q000378:metabolism*; D056004:Molecular Dynamics Simulation; D008969:Molecular Sequence Data; D018272:Porins / Q000737:chemistry* / Q000378:metabolism; D011485:Protein Binding; D017433:Protein Structure, Secondary; D017434:Protein Structure, Tertiary; D047090:beta-Lactams / Q000737:chemistry* / Q000378:metabolism / Q000494:pharmacology
chemical_list: D000900:Anti-Bacterial Agents; C109237:OmpF protein; D018272:Porins; D047090:beta-Lactams; D000667:Ampicillin; D000077727:Ertapenem; D002228:Carbenicillin