Mechanism and Molecular Design Principles of Cationic Surfactants: From Charge-Driven Membrane Interactions to Next-Generation Quaternary Ammonium Compounds.

Cationic surfactants, in particular quaternary ammonium compounds (QACs), represent one of the most relevant and broadly applied classes of antiseptics. Their antimicrobial activity arises from electrostatic interactions with microbial membranes, resulting in rapid disruption of the membrane structure. In this review, we summarize currently described mechanistic insights into the membrane active behavior of QACs, thereby focusing on the interplay between molecular architecture, supramolecular organization and antimicrobial efficacy. Key structure activity relationships (SARs) are discussed, including the role of the hydrophobic tail length, spacer design, charge density and distribution, and counterion effects. Addressing challenges such as antimicrobial resistance and biocompatibility requires a detailed understanding of SARs and the mechanism behind resistance development. Therefore, we further highlight emerging concepts such as cleavable linkers, hybrid systems integrating metal, peptide or photodynamic modalities, supramolecular aggregates, and the integration of biodegradable materials for the design of surfactants capable of overcoming bacterial resistance and tuning selectivity toward bacterial cells. This review provides an updated framework for developing next-generation QACs that preserve antimicrobial potency while minimizing toxicity and the evolution of resistant microbial populations.