Natamycin interferes with ergosterol-dependent lipid phases in model membranes

Area of Science:

• Biochemistry
• Biophysics
• Membrane Biology

Background:

• Natamycin is an antifungal polyene macrolide used as a food preservative and for treating fungal infections.
• Its precise mechanism of action, especially its non-pore-forming activity, remains poorly understood.

Purpose of the Study:

• To elucidate the molecular mechanism of natamycin's antifungal action.
• To investigate natamycin's interaction with membrane sterols and its effect on membrane properties.

Main Methods:

• Nuclear magnetic resonance (NMR) spectroscopy of deuterated sterols and lipids.
• Molecular dynamics (MD) simulations.
• Ultraviolet-sensitive microscopy of giant unilamellar vesicles (GUVs).

Main Results:

• Natamycin slows sterol mobility in liquid-ordered (Lo) membranes and impacts water permeability.
• Natamycin disrupts sterol-dependent lipid packing, increasing membrane solvent accessibility, especially in ergosterol-containing membranes.
• Natamycin exhibits higher affinity for the Lo phase in GUVs containing ergosterol, suggesting specific interaction with sterol-enriched domains.

Conclusions:

• Natamycin specifically interacts with sterol-induced ordered membrane phases.
• Disruption of lipid packing and increased solvent accessibility in ergosterol-rich membranes likely underlies natamycin's selective antifungal efficacy.