title: Interaction of 31 beta-lactam antibiotics with the H+/peptide symporter PEPT2: analysis of affinity constants and comparison with PEPT1.
abstract: The activity of the renal peptide transporters PEPT2 and PEPT1 determines-among other factors such as metabolic stability in liver and plasma-the circulatory half-life of penicillins and cephalosporins during therapy. This study was initiated to examine systematically the interaction of beta-lactam antibiotics with PEPT2. Interaction of 31 cephalosporins and penicillins with the carrier protein was characterized by measuring their ability to inhibit the uptake of [(14)C]Gly-Sar into renal SKPT cells. Cefadroxil, cefaclor, cyclacillin, cephradine, cephalexin and moxalactam were recognized by PEPT2 with very high affinity comparable to that of natural dipeptides (K(i)=3-100microM). Ceftibuten, dicloxacillin, amoxicillin, metampicillin, cloxacillin, ampicillin, cefixime, cefamandole, oxacillin and cefmetazole interacted with PEPT2 with medium affinity (K(i)=0.1-5mM). For the other beta-lactam antibiotics studied interaction was very low or not measurable (K(i)>5mM). The affinity constants of beta-lactam antibiotics at rPEPT2 and hPEPT1 are significantly correlated, but the rank orders are not identical. Decisive differences between PEPT1 and PEPT2 recognition of the N-terminal part of the compounds became evident. Moreover, this large data set of affinity constants of beta-lactam antibiotics will be useful for structure-transport (binding) analyses of PEPT2.
authors.affiliation: Membrane Transport Group, Biozentrum of the Martin-Luther-University Halle-Wittenberg, Halle/Saale, Germany.
authors.forename: Petra
authors.initials: P
authors.lastname: Luckner
authors.forename: Matthias
authors.initials: M
authors.lastname: Brandsch
mesh_terms: D000818:Animals; D000900:Anti-Bacterial Agents / Q000737:chemistry / Q000378:metabolism*; D001665:Binding Sites / Q000502:physiology; D018938:Caco-2 Cells; D004305:Dose-Response Relationship, Drug; D006801:Humans; D000074011:Peptide Transporter 1; D011485:Protein Binding / Q000502:physiology; D051381:Rats; D027981:Symporters / Q000378:metabolism*; D047090:beta-Lactams / Q000737:chemistry / Q000378:metabolism*
chemical_list: D000900:Anti-Bacterial Agents; D000074011:Peptide Transporter 1; C082186:SLC15A1 protein, human; D027981:Symporters; D047090:beta-Lactams; C093694:hydrogen-coupled oligopeptide transporter PepT2