title: Several hPepT1-transported drugs are substrates of the Escherichia coli proton-coupled oligopeptide transporter YdgR.
abstract: Proton-dependent oligopeptide transporters (POTs) are secondary active transporters found in all kingdoms of life. POTs utilize the proton electrochemical gradient for the uptake of nutrient dipeptides and tripeptides. The human POT hPepT1 is known to transport a number of drugs. As part of ongoing studies on substrate specificities of POTs from Escherichia coli, our aim in this study was to investigate whether bacterial POTs could also transport these drugs. For this, we selected the common orally administered drugs sulpiride, bestatin, valacyclovir, ampicillin and oseltamivir, that are all transported by hPepT1. The transport of these drugs was evaluated using the prototypical POT YdgR from E. coli. The transport studies were pursued through combining cell-based assays with liquid chromatography-tandem mass spectrometric (LC-MS/MS) analysis. These investigations revealed that YdgR from E. coli is able to transport five (sulpiride, bestatin, valacyclovir, ampicillin and oseltamivir) drugs. Furthermore, cells not overexpressing YdgR were also able to transport these drugs in a POT-like manner. Orthologues of YdgR are found in several species in the gut microbiome; hence, our findings could have implications for further understanding about the interaction between gut microbes and orally administered drugs.
authors.affiliation: Department of Drug Design and Pharmacology, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark.
authors.forename: Bala K
authors.initials: BK
authors.lastname: Prabhala
authors.affiliation: Department of Drug Design and Pharmacology, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark.
authors.forename: Nanda G
authors.initials: NG
authors.lastname: Aduri
authors.affiliation: Health Biotechnology Division, National Institute for Biotechnology and Genetic Engineering, Faisalabad, Pakistan.
authors.forename: Mazhar
authors.initials: M
authors.lastname: Iqbal
authors.affiliation: Health Biotechnology Division, National Institute for Biotechnology and Genetic Engineering, Faisalabad, Pakistan.
authors.forename: Moazur
authors.initials: M
authors.lastname: Rahman
authors.affiliation: Department of Drug Design and Pharmacology, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark.
authors.forename: Michael
authors.initials: M
authors.lastname: Gajhede
authors.affiliation: Department of Drug Design and Pharmacology, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark.
authors.forename: Paul R
authors.initials: PR
authors.lastname: Hansen
authors.affiliation: Department of Drug Design and Pharmacology, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark. Electronic address: om@sund.ku.dk.
authors.forename: Osman
authors.initials: O
authors.lastname: Mirza
mesh_terms: D000212:Acyclovir / Q000031:analogs & derivatives / Q000378:metabolism; D001692:Biological Transport; D004926:Escherichia coli / Q000378:metabolism*; D029968:Escherichia coli Proteins / Q000235:genetics / Q000378:metabolism*; D000069196:Gastrointestinal Microbiome / Q000187:drug effects; D006801:Humans; D026901:Membrane Transport Proteins / Q000235:genetics / Q000378:metabolism*; D009842:Oligopeptides / Q000378:metabolism; D000074011:Peptide Transporter 1 / Q000235:genetics / Q000378:metabolism*; D004364:Pharmaceutical Preparations / Q000378:metabolism*; D011522:Protons; D013379:Substrate Specificity; D013469:Sulpiride / Q000378:metabolism; D000077483:Valacyclovir; D014633:Valine / Q000031:analogs & derivatives / Q000378:metabolism
chemical_list: D029968:Escherichia coli Proteins; D026901:Membrane Transport Proteins; D009842:Oligopeptides; D000074011:Peptide Transporter 1; D004364:Pharmaceutical Preparations; D011522:Protons; C518647:dtpA protein, E coli; D013469:Sulpiride; D014633:Valine; D000077483:Valacyclovir; D000212:Acyclovir
keywords: Bacteria/drug interaction; Bacterial peptide transporters; hPepT1 drugs