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Lateral opening site of human oligopeptide transporter 2 plays a key role in the interaction with polymyxins.
eLife · · Journal Article · Open access
Jiang, Luo + more
Abstract ↗AI summary
The abstract is read at the publisher; the summary is JClub's.
Alanine substitution at Dab3 in polymyxins reduces nephrotoxicity in mice while retaining antibacterial activity, guided by an hPepT2 lateral-opening interaction model.
- Why it matters: Polymyxins are last-line therapy for MDR Gram-negative infections, but kidney toxicity limits use; the molecular interaction with hPepT2 in renal reabsorption is unclear.
- What they did: The authors integrated bioinformatic modeling, transporter mutagenesis, and molecular analyses to map polymyxin binding at hPepT2’s lateral opening, implicating residues including D215, and then synthesized Dab1/Dab3/Dab5/Dab9-modified analogs.
- The result: Dab3 alanine lowered hPepT2 interaction and nephrotoxicity in mice without losing antibacterial activity, supporting the hPepT2–polymyxin structure–interaction relationship as a strategy to design safer lipopeptide antibiotics.
The findingWhy it mattersWhat they didThe result
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