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Triggering the Amphotericin B Pore-Forming Activity by Phytochemicals.
Svetlana S Efimova1, Anna I Malykhina1, Olga S Ostroumova1
1Laboratory of Membrane and Ion Channel Modeling, Institute of Cytology of Russian Academy of Sciences, Tikhoretsky 4, 194064 Saint Petersburg, Russia.
Membranes
|July 28, 2023
Summary
Plant compounds can enhance the antifungal drug amphotericin B (AmB) by increasing its pore-forming activity in fungal membranes. This approach may reduce AmB toxicity and improve treatment efficacy for systemic mycoses.
Area of Science:
- Pharmacology and Toxicology
- Mycology and Infectious Diseases
- Natural Product Chemistry
Background:
- Amphotericin B (AmB) is a crucial antifungal agent for systemic mycoses, valued for its broad spectrum and low resistance development.
- AmB's clinical utility is limited by significant toxicity, including nephropathy and hemolysis, often necessitating reduced therapeutic doses.
- Exploring AmB potentiation with natural compounds offers a strategy to maintain efficacy while mitigating toxicity.
Purpose of the Study:
- To investigate the potential of plant-derived polyphenols and alkaloids in enhancing the antifungal activity of amphotericin B.
- To evaluate the impact of these phytochemicals on AmB's pore-forming capabilities and membrane interactions.
- To assess the therapeutic potential of AmB-phytochemical combinations for reducing drug toxicity.
Main Methods:
- Utilized transmembrane current measurements in lipid bilayers (palmitoyloleoylphosphocholine and ergosterol) to assess AmB activity.
- Screened various plant polyphenols and alkaloids for their effect on AmB-induced transmembrane currents.
- Employed absorbance spectroscopy and differential scanning microcalorimetry to investigate AmB-membrane interactions and lipid properties.
Main Results:
- Several phytochemicals, including phloretin, quercetin, and resveratrol, significantly increased AmB-induced transmembrane currents in ergosterol-containing membranes.
- Other compounds like cardamonin and curcumin inhibited AmB activity, while some showed no significant effect.
- Potentiation effects were largely lost when ergosterol was replaced with cholesterol, suggesting reduced toxicity potential against mammalian cells.
Conclusions:
- Specific plant polyphenols and alkaloids can enhance the pore-forming and antifungal activity of amphotericin B by altering membrane properties.
- These synergistic interactions appear specific to ergosterol-rich fungal membranes, indicating a potential mechanism for reduced host toxicity.
- Combinations of amphotericin B with identified plant molecules represent a promising avenue for developing safer and more effective antifungal therapies.
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