Trends in optimizing antibacterial cationic amphiphiles

Abstract Cationic amphiphiles are investigated as antibacterials, yet their potential is often limited by host-cell toxicity. Bacterial and mammalian membranes share core physicochemical features that promote interactions with cationic amphiphiles. Selectivity is realistically understood as a relative property window. This review summarizes recent trends in the design of antibacterial cationic amphiphiles, focusing on quaternary ammonium compounds, lipopeptides and dendritic amphiphiles. Across these structurally diverse compound classes, tuning charge density, hydrophobicity, degradability, lipid selectivity, and supramolecular properties emerge as design approaches to improve antibacterial potency and reduce toxicity. Recent developments exploit bacterial lipids and lipid membrane surfaces as targets and employ design strategies to improve selectivity, such as multivalent presentation of cationic groups, optimization of membrane insertion, and combinations of membrane-targeting building blocks. Cationic amphiphiles inserting into bacterial membranes can induce permeabilization, dissipation of the proton motive force, and disruption of energy homeostasis, suggesting these processes represent a common mechanistic framework linking physical membrane damage to antibacterial activity. Complementing phenotypic screenings by mechanistic studies and concentration-dependent mode-of-action profiling across compound series is a promising future direction. Understanding how molecular structure governs membrane interactions and bacterial physiology will support the development of next-generation cationic amphiphiles with improved potency, selectivity and translational potential.