Lateral opening site of human oligopeptide transporter 2 plays a key role in the interaction with polymyxins
6 affiliations
- 1National Glycoengineering Research Center, Shandong University, Qingdao, China
- 2Molecular Drug Development Group, Sydney Pharmacy School, Faculty of Medicine and Health, The University of Sydney, Sydney, Australia
- 3Biomedicine Discovery Institute, Infection Program, Monash University, Melbourne, Australia
- 4Division of Infectious Diseases and Tropical Medicine, Department of Medicine, Faculty of Medicine Siriraj Hospital, Mahidol University, Bangkok, Thailand
- 5Department of Industrial and Molecular Pharmaceutics, College of Pharmacy, Purdue University, West Lafayette, United States
- 6Save Sight Institute, Faculty of Medicine and Health, The University of Sydney, Sydney, Australia
Abstract
Multidrug-resistant (MDR) Gram-negative bacteria pose a critical global health threat, while polymyxins remain a last-line therapy. However, their clinical use is limited by nephrotoxicity. Human oligopeptide transporter 2 (hPepT2) is a membrane transporter mediating the reabsorption of polymyxins in renal cells and contributes to their nephrotoxicity, but the molecular basis of their interaction remains unclear. Here, we investigated the structure-interaction relationship (SIR) of polymyxins with hPepT2 by integrating computational, chemical, and cell biology approaches. Bioinformatic modeling predicted an outward-facing hPepT2 structure and a potential transport pathway, with polymyxins interacting at the lateral opening, particularly E214, D215, D317, D342, and E622. Transporter mutagenesis and molecular analyses confirmed that D215 is critical for polymyxin binding, while other residues influence transporter turnover and/or expression. We subsequently synthesized polymyxin analogs with modifications at Dab1, Dab3, Dab5, and Dab9 of polymyxins, which reduced interactions with hPepT2. Notably, alanine substitution at Dab3 reduced nephrotoxicity in mice while retaining antibacterial activity. Overall, this proof-of-concept study demonstrates that the hPepT2-polymyxin SIR model provides a viable strategy for developing novel, safer lipopeptide antibiotics.
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BibTeX
@article{jiang2026lateral,
title = {{Lateral opening site of human oligopeptide transporter 2 plays a key role in the interaction with polymyxins}},
author = {Xukai Jiang and Yining Luo and Mohammad AK Azad and Limei Xu and Min Xiao and Tony Velkov and Kade D Roberts and Visanu Thamlikitkul and Qi Tony Zhou and Fanfan Zhou and Jian Li},
journal = {eLife},
year = {2026},
month = oct,
doi = {10.7554/elife.111387},
url = {https://elifesciences.org/articles/111387},
note = {CC BY 4.0},
}
RIS
TY - JOUR
TI - Lateral opening site of human oligopeptide transporter 2 plays a key role in the interaction with polymyxins
AU - Xukai Jiang
AU - Yining Luo
AU - Mohammad AK Azad
AU - Limei Xu
AU - Min Xiao
AU - Tony Velkov
AU - Kade D Roberts
AU - Visanu Thamlikitkul
AU - Qi Tony Zhou
AU - Fanfan Zhou
AU - Jian Li
PY - 2026
DA - 2026/10/29
JO - eLife
DO - 10.7554/elife.111387
UR - https://elifesciences.org/articles/111387
AB - Multidrug-resistant (MDR) Gram-negative bacteria pose a critical global health threat, while polymyxins remain a last-line therapy. However, their clinical use is limited by nephrotoxicity. Human oligopeptide transporter 2 (hPepT2) is a membrane transporter mediating the reabsorption of polymyxins in renal cells and contributes to their nephrotoxicity, but the molecular basis of their interaction remains unclear. Here, we investigated the structure-interaction relationship (SIR) of polymyxins with hPepT2 by integrating computational, chemical, and cell biology approaches. Bioinformatic modeling predicted an outward-facing hPepT2 structure and a potential transport pathway, with polymyxins interacting at the lateral opening, particularly E214, D215, D317, D342, and E622. Transporter mutagenesis and molecular analyses confirmed that D215 is critical for polymyxin binding, while other residues influence transporter turnover and/or expression. We subsequently synthesized polymyxin analogs with modifications at Dab1, Dab3, Dab5, and Dab9 of polymyxins, which reduced interactions with hPepT2. Notably, alanine substitution at Dab3 reduced nephrotoxicity in mice while retaining antibacterial activity. Overall, this proof-of-concept study demonstrates that the hPepT2-polymyxin SIR model provides a viable strategy for developing novel, safer lipopeptide antibiotics.
SN - 2050-084X
ER -