Mechanistic Insights into Lipooligourea-Lipid Membrane Interactions.

Area of Science:

• Biophysical chemistry
• Antimicrobial drug discovery
• Synthetic biology

Background:

• Developing novel antimicrobials is crucial to combat bacterial resistance.
• Synthetic peptidomimetics offer a promising avenue for new therapeutics.
• Understanding their interaction with bacterial membranes is key.

Purpose of the Study:

• To investigate the membrane-disruptive behavior of C10-OU4, a cationic lipooligourea foldamer.
• To elucidate the concentration-dependent interactions of C10-OU4 with model bacterial membranes.
• To establish a foundation for designing novel membrane-active foldamer antibiotics.

Main Methods:

• Langmuir monolayer analysis
• Quartz crystal microbalance with dissipation monitoring (QCM-D)
• Attenuated total reflection-Fourier transform infrared spectroscopy (ATR-FTIR)

Main Results:

• At low concentrations (1 μM), C10-OU4 adsorbs to the membrane surface with minor headgroup perturbations.
• At 5 μM, significant acyl chain disorder and partial membrane solubilization occur.
• At 10 μM (near MIC), extensive membrane disintegration and altered foldamer insertion geometries are observed.

Conclusions:

• C10-OU4 exhibits a multimodal mechanism of action, transitioning from surface association to bilayer disruption.
• Concentration dictates the extent and nature of membrane interaction.
• These findings provide insights into foldamer-membrane physicochemical interactions for rational drug design.