Molecular Interactions of Polyene Antibiotics with Lipid Membranes

Polyene antibiotics are a class of amphipathic macrolides renowned for their potent antifungal properties. Their activity principally derives from a high affinity for ergosterol, the principal sterol in fungal membranes, and a lower affinity for cholesterol in mammalian membranes. Upon encountering a lipid bilayer, polyene molecules can assemble into defined supramolecular structures that either extract ergosterol into extramembranous aggregates or insert as transmembrane pores. These processes compromise membrane integrity, causing ionic dysregulation and cell death. The balance between pore formation and sterol sequestration underpins both therapeutic efficacy and host toxicity. Molecular imaging and biophysical analyses have elucidated how sterol composition, membrane thickness and lipid packing govern selective binding and insertion. Insights into the thermodynamics of polyene self-association in aqueous environments highlight the role of oligomer size in determining membrane selectivity. Advances in liposomal encapsulation, sterol-targeted derivatives and combinatorial approaches are extending the clinical utility of polyenes by reducing toxicity, improving solubility and overcoming resistance. A comprehensive understanding of polyene–lipid interactions at the molecular scale is therefore critical for the rational design of next-generation antifungal agents.

Research from Nature Portfolio

High-resolution fluorescence lifetime imaging has revealed dual modes of action for amphotericin B: formation of small extramembranous aggregates that extract ergosterol and direct insertion into the bilayer to form ion-conducting pores. Detailed structural studies in single lipid bilayers have demonstrated that ergosterol markedly promotes the formation of supramolecular antibiotic assemblies and their penetration into the membrane core, whereas cholesterol attenuates this effect, offering a molecular basis for fungal selectivity. Complementary molecular dynamics simulations have characterised the early stages of amphotericin B dimerisation in aqueous solution, showing that rapid interconversion between parallel and antiparallel dimers precedes higher-order oligomer formation. These oligomers are implicated in non-specific membrane insertion, thereby modulating both efficacy and toxicity. Collectively, these foundational investigations provide an integrated view of how polyene aggregation state, sterol affinity and membrane environment converge to determine antifungal activity.

Molecular Interactions of Polyene Antibiotics with Lipid Membranes publication trend

The graph below shows the total number of articles in molecular interactions of polyene antibiotics with lipid membranes across all publications each year (not limited to Nature Index journals).

Technical terms

Ergosterol: A fungal membrane sterol that binds polyene antibiotics with high specificity.

Pore formation: Assembly of antibiotic molecules into transmembrane channels permitting uncontrolled ion flux.

Extramembranous aggregate: A supramolecular assembly of polyene molecules that extracts sterol molecules from the lipid bilayer.

Liposomal formulation: Encapsulation of an antibiotic within lipid vesicles to modulate release, reduce toxicity and improve solubility.

References

1. Reviving the interest in the versatile drug nystatin: A multitude of strategies to increase its potential as an effective and safe antifungal agent. Advanced Drug Delivery Reviews (2023).
2. Gladiolin produced by pathogenic Burkholderia synergizes with amphotericin B through membrane lipid rearrangements. mBio (2024).
3. Molecular organization, localization and orientation of antifungal antibiotic amphotericin B in a single lipid bilayer. Scientific Reports (2016).
4. Recent progress in the study of the interactions of amphotericin B with cholesterol and ergosterol in lipid environments. European Biophysics Journal (2014).
5. Sterol Sponge Mechanism Is Conserved for Glycosylated Polyene Macrolides. ACS Central Science (2021).
6. Thermodynamics and kinetics of amphotericin B self-association in aqueous solution characterized in molecular detail. Scientific Reports (2016).