Modular Triethylene Glycol Decouples Antimicrobial Potency from Cytotoxicity in Membrane-Active Drugs
5 affiliations
- 1Technical University Dortmund , , ,
- 2Max Planck Institute of Molecular Physiology , , ,
- 3Rhine-Waal University of Applied Sciences , , ,
- 4University of Potsdam , , ,
- 5University Hospital Münster , , ,
Abstract
Cationic membrane-active drugs are an important focus of antibiotic research, yet their potential is often limited by poor selectivity. Here, we establish steric protection of cations by modular triethylene glycol as a chemical design framework to decouple antimicrobial potency from cytotoxicity. Using antipsychotics, a class of widely prescribed membrane-active drugs, we show that lipophilicity and rigidity jointly govern antimicrobial potency and mammalian cell cytotoxicity. Membrane perturbation emerged as a key determinant of bioactivity and revealed physicochemical windows that decouple antimicrobial potency and cytotoxicity. Our findings spotlight octanol as a design motif for steric protection of cations that emerged from systematic tuning of side chain lipophilicity and mimics a known metabolite motif. As exemplified with the model drug chlorpromazine, this modification can maintain water solubility, improve membrane engagement, reduce mammalian cell cytotoxicity, enhance antibacterial potency, and amplify polymyxin amplification across Gram-negative bacteria, including drug-resistant clinical isolates. Our findings indicate that membrane remodeling associated with polymyxin resistance in Escherichia coli correlates with a collateral vulnerability to cationic amphiphiles, suggesting a physicochemically tractable consequence of resistance. These findings establish a chemical design framework for small-molecule cationic amphiphiles with improved physicochemical properties, membrane engagement, and bioactivity that can be difficult to achieve by traditional alkylation.
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BibTeX
@article{seewald2026modular,
title = {{Modular Triethylene Glycol Decouples Antimicrobial Potency from Cytotoxicity in Membrane-Active Drugs}},
author = {Marc Seewald and Marla Stamen and Jian Li and Sven Engelkamp and Jan-Simon Behnke and Ralf Lucassen and Katharina Borowick and Marie Weilburg and Virginia Wycisk and Tom Fielitz and Tzu-Chien Wu and Matthias Hartlieb and Frieder Schaumburg and Dirk Bockmühl and Tobias Raisch and Leonhard Hagen Urner},
journal = {JACS Au},
year = {2026},
month = oct,
doi = {10.1021/jacsau.6c01288},
url = {https://pubs.acs.org/jaaucr/article/6/10/5949/5448597/Modular-Triethylene-Glycol-Decouples-Antimicrobial},
note = {CC BY-NC-ND 4.0},
}
RIS
TY - JOUR
TI - Modular Triethylene Glycol Decouples Antimicrobial Potency from Cytotoxicity in Membrane-Active Drugs
AU - Marc Seewald
AU - Marla Stamen
AU - Jian Li
AU - Sven Engelkamp
AU - Jan-Simon Behnke
AU - Ralf Lucassen
AU - Katharina Borowick
AU - Marie Weilburg
AU - Virginia Wycisk
AU - Tom Fielitz
AU - Tzu-Chien Wu
AU - Matthias Hartlieb
AU - Frieder Schaumburg
AU - Dirk Bockmühl
AU - Tobias Raisch
AU - Leonhard Hagen Urner
PY - 2026
DA - 2026/10/11
JO - JACS Au
DO - 10.1021/jacsau.6c01288
UR - https://pubs.acs.org/jaaucr/article/6/10/5949/5448597/Modular-Triethylene-Glycol-Decouples-Antimicrobial
AB - Cationic membrane-active drugs are an important focus of antibiotic research, yet their potential is often limited by poor selectivity. Here, we establish steric protection of cations by modular triethylene glycol as a chemical design framework to decouple antimicrobial potency from cytotoxicity. Using antipsychotics, a class of widely prescribed membrane-active drugs, we show that lipophilicity and rigidity jointly govern antimicrobial potency and mammalian cell cytotoxicity. Membrane perturbation emerged as a key determinant of bioactivity and revealed physicochemical windows that decouple antimicrobial potency and cytotoxicity. Our findings spotlight octanol as a design motif for steric protection of cations that emerged from systematic tuning of side chain lipophilicity and mimics a known metabolite motif. As exemplified with the model drug chlorpromazine, this modification can maintain water solubility, improve membrane engagement, reduce mammalian cell cytotoxicity, enhance antibacterial potency, and amplify polymyxin amplification across Gram-negative bacteria, including drug-resistant clinical isolates. Our findings indicate that membrane remodeling associated with polymyxin resistance in Escherichia coli correlates with a collateral vulnerability to cationic amphiphiles, suggesting a physicochemically tractable consequence of resistance. These findings establish a chemical design framework for small-molecule cationic amphiphiles with improved physicochemical properties, membrane engagement, and bioactivity that can be difficult to achieve by traditional alkylation.
SN - 2691-3704
ER -