Structural basis for antibiotic transport and inhibition in PepT2

• Published in: Nature communications 2024-10, Vol.15 (1), p.8755-14, Article 8755
• Main Authors: Parker, Joanne L., Deme, Justin C., Lichtinger, Simon M., Kuteyi, Gabriel, Biggin, Philip C., Lea, Susan M., Newstead, Simon
• Format: Article
• Language: English
• Subjects: 101/28; 631/154/433; 631/45; 631/535/1258/1259; 631/57; 82/83; Amides; Amoxicillin; Amoxicillin - chemistry; Amoxicillin - metabolism; Amoxicillin - pharmacokinetics; Animals; Anti-Bacterial Agents - chemistry; Anti-Bacterial Agents - pharmacokinetics; Antibacterial agents; Antibiotics; Bioavailability; Biological Transport; Cefadroxil - chemistry; Cefadroxil - metabolism; Cefadroxil - pharmacokinetics; Cloxacillin; Cryoelectron Microscopy; Drug development; Drugs; Gram-positive bacteria; Humanities and Social Sciences; Humans; Ligands; Molecular dynamics; Molecular Dynamics Simulation; multidisciplinary; Peptide mapping; Peptide transporter; Peptides; Pharmacokinetics; Protonation; Protons; Rats; Recognition; Science; Science (multidisciplinary); Symporters - chemistry; Symporters - metabolism; β-Lactam antibiotics
• ISSN: 2041-1723; 2041-1723
• DOI: 10.1038/s41467-024-53096-6

The uptake and elimination of beta-lactam antibiotics in the human body are facilitated by the proton-coupled peptide transporters PepT1 (SLC15A1) and PepT2 (SLC15A2). The mechanism by which SLC15 family transporters recognize and discriminate between different drug classes and dietary peptides remains unclear, hampering efforts to improve antibiotic pharmacokinetics through targeted drug design and delivery. Here, we present cryo-EM structures of the proton-coupled peptide transporter, PepT2 from Rattus norvegicus , in complex with the widely used beta-lactam antibiotics cefadroxil, amoxicillin and cloxacillin. Our structures, combined with pharmacophore mapping, molecular dynamics simulations and biochemical assays, establish the mechanism of beta-lactam antibiotic recognition and the important role of protonation in drug binding and transport. The uptake and elimination of beta-lactam antibiotics are facilitated by the proton-coupled peptide transporters. Here authors present cryo-EM structures of PepT2 in complex with the cefadroxil, amoxicillin and cloxacillin to reveal a mechanism of beta-lactam antibiotic recognition