Multivalent amphiphilic cyclodextrins for selective membrane disruption with potent antifungal activity

Area of Science:

• Supramolecular chemistry
• Medicinal chemistry
• Chemical biology

Background:

• Fungal infections pose significant health risks, necessitating novel antifungal agents.
• Current antifungal therapies often suffer from limited selectivity and host toxicity.
• Targeting fungal membranes offers a promising strategy for developing new treatments.

Purpose of the Study:

• To engineer multivalent amphiphilic cyclodextrins as novel supramolecular interfacial disruptors.
• To achieve selective destabilization of fungal membranes.
• To decouple antifungal efficacy from host cell (hemolysis) toxicity.

Main Methods:

• Synthesis of multivalent amphiphilic cyclodextrins with tunable cationic and hydrophobic properties.
• Investigation of their interaction with fungal and red blood cell membranes.
• Assessment of membrane destabilization mechanisms, including surfactant-like collapse versus channel formation.
• Evaluation of antifungal activity and hemolytic activity.

Main Results:

• Engineered cyclodextrins demonstrated selective disruption of fungal membranes.
• The mechanism involved cooperative cationic-hydrophobic tuning, inducing a surfactant-like membrane collapse.
• This mechanism was distinct from the channel formation typically observed with polyene antifungals.
• Precise control over multivalency successfully decoupled antifungal potency from hemolytic activity.

Conclusions:

• Multivalent amphiphilic cyclodextrins act as effective supramolecular interfacial disruptors for selective fungal membrane destabilization.
• The developed platform allows for the design of membrane-active molecules with improved selectivity.
• This approach offers a promising strategy for developing safer and more effective antifungal therapies.