Mechanistic Insights into Lipooligourea-Lipid Membrane Interactions.

Understanding how synthetic peptidomimetics interact with bacterial membranes is key to developing next-generation antimicrobials. In this study, we investigate the membrane-disruptive behavior of C10-OU4, a cationic lipooligourea foldamer that mimics the amphiphilic architecture of antimicrobial lipopeptides. Using a multitechnique approach─Langmuir monolayer analysis, quartz crystal microbalance with dissipation monitoring (QCM-D), and attenuated total reflection-Fourier transform infrared spectroscopy (ATR-FTIR)─we probe the concentration-dependent interactions of C10-OU4 with lipid membranes that model Gram-positive bacterial membranes. At low concentrations (1 μM), C10-OU4 adsorbs to the membrane surface, inducing minor structural perturbations limited to the polar headgroup region. Increasing the concentration to 5 μM results in significant acyl chain disorder, partial membrane solubilization, and likely, micelle-like aggregate formation, as evidenced by QCM-D frequency shifts and ATR-FTIR data. At 10 μM, near the minimal inhibitory concentration, membrane disintegration becomes extensive, with the lipooligourea adopting orientations suggestive of random or tilted insertion geometries. These findings support a multimodal mechanism of action that transitions from surface association to full bilayer disruption in a concentration-dependent manner. The combined use of structural and dynamic measurements provides detailed insight into the physicochemical principles underlying lipooligourea-membrane interactions, offering a foundation for the rational design of membrane-active foldamer antibiotics.