Modular Triethylene Glycol Decouples Antimicrobial Potency from Cytotoxicity in Membrane-Active Drugs

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.