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The interaction of plant flavones with amphotericin B: Consequences for its pore-forming ability
Anna I Malykhina1, Svetlana S Efimova1, Vladimir S Andriianov1
1Laboratory of Membrane and Ion Channel Modeling, Institute of Cytology of Russian Academy of Sciences, Tikhoretsky 4, Saint Petersburg 194064, Russian Federation.
Abstract:
The growth of antibiotic resistance to antifungal drugs contributes to the search for new ways to enhance their effectiveness and reduce toxicity. The undeniable advantage of polyene macrolide antibiotic amphotericin B (AmB) which ensures low pathogen resistance is its mechanism of action related to the formation of transmembrane pores in target lipid membranes. Here, we investigated the effects of plant flavones, chrysin, wogonin, baicalein, apigenin, scutellarein, luteolin, morin and fisetin on the pore-forming activity of AmB in the sterol-enriched membranes by electrophysiological assays. Сhrysin, wogonin, baicalein, apigenin, scutellarein, and luteolin were shown to decrease the AmB pore-forming activity in the bilayers composed of palmitoyloleylphosphocholine independently of their sterol composition. Morin and fisetin led to the increase and decrease in the AmB pore-forming activity in the ergosterol- and cholesterol-containing bilayers respectively. Differential scanning microcalorimetry of the gel-to-liquid crystalline phase transition of membrane forming lipids, molecular dynamics simulations, and absorbance spectroscopy revealed the possibility of direct interactions between AmB and some flavones in the water and/or in the lipid bilayer. The influence of these interactions on the antibiotic partitioning between aqueous solution and membrane and/or its transition between different states in the bilayer was discussed.
Insights
Plant flavones can modify the antifungal drug amphotericin B (AmB) pore formation in cell membranes. Some flavones decrease AmB activity, while others alter it depending on membrane sterols, offering new strategies against fungal infections.
Area of Science:
- Biochemistry
- Pharmacology
- Membrane Biophysics
Background:
- Antifungal drug resistance necessitates novel therapeutic strategies.
- Amphotericin B (AmB), a polyene macrolide, exhibits low resistance due to its pore-forming mechanism in lipid membranes.
- Plant-derived flavones are investigated for their potential to modulate drug activity.
Purpose of the Study:
- To investigate the impact of various plant flavones on the pore-forming activity of amphotericin B (AmB) in sterol-enriched membranes.
- To elucidate the interaction mechanisms between AmB and flavones in lipid bilayers.
- To assess the potential of flavones in enhancing AmB efficacy or reducing its toxicity.
Main Methods:
- Electrophysiological assays to measure AmB pore formation.
- Differential scanning microcalorimetry to study lipid phase transitions.
- Molecular dynamics simulations to model AmB-flavone interactions.
- Absorbance spectroscopy to analyze interactions in aqueous and lipid environments.
Main Results:
- Chrysin, wogonin, baicalein, apigenin, scutellarein, and luteolin reduced AmB pore formation in palmitoyloleylphosphocholine bilayers, irrespective of sterol content.
- Morin and fisetin differentially affected AmB pore formation: morin increased it in ergosterol bilayers, while fisetin decreased it in cholesterol bilayers.
- Evidence suggests direct interactions between AmB and certain flavones in aqueous and/or lipid phases, influencing AmB's membrane partitioning and state transitions.
Conclusions:
- Specific plant flavones can modulate the membrane pore-forming activity of amphotericin B.
- The sterol composition of the membrane influences the interaction between AmB and certain flavones.
- These findings suggest potential therapeutic applications for flavone-AmB combinations to combat fungal infections and overcome drug resistance.
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