16.10.2024

Decoding antibiotic transport through SLC15A2

Why are some antibiotics more effectively absorbed in the body than others, even within the same class?

Beta-lactam antibiotics, such as penicillins and cephalosporins, are among the most widely used drugs to combat bacterial infections. However, their effectiveness depends not only on their ability to kill bacteria but also on how well they are absorbed and transported within the body. Proton-coupled peptide transporters like SLC15A2 (PepT2) play a crucial role in the uptake of these antibiotics, yet the mechanisms by which these transporters recognize and handle different antibiotics remain unclear.

In a recent study, researchers used cryo-EM to resolve the structure of SLC15A2 from Rattus norvegicus in complex with three widely used beta-lactam antibiotics: cefadroxil, amoxicillin, and cloxacillin. By combining structural analysis with pharmacophore mapping, molecular dynamics simulations, and biochemical assays, the team uncovered the molecular mechanisms by which SLC15A2 recognizes these antibiotics. A key discovery was the role of protonation in orienting beta-lactam antibiotics within the transporter’s binding site, with the primary amine group playing a crucial role in facilitating drug binding and transport.

Interestingly, SSM-based electrophysiology assay (SURFE²R) showed that while cefadroxil and amoxicillin were efficiently transported by SLC15A2, cloxacillin behaved differently, acting as a competitive inhibitor. Structural analysis revealed that cloxacillin failed to engage the key electrostatic interactions necessary for transport, instead blocking the channel and preventing the passage of other substrates.

In conclusion, by decoding how beta-lactam antibiotics interact with SLC15A2, this research offers a new pharmacophore model to guide the design of more effective antibiotics and improve drug delivery strategies.

Find the full article here: Structural basis for antibiotic transport and inhibition in PepT2

Learn more about SSM-Based Electrophysiology and SURFE²R devices here: https://www.nanion.de/products/surfe2r-n1/