Natamycin interferes with ergosterol-dependent lipid phases in model membranes
Natamycin is an antifungal polyene macrolide that is used as a food preservative but also to treat fungal keratitis and other yeast infections. In contrast to other polyene antimycotics, natamycin does not form ion pores in the plasma membrane, but its mode of action is poorly understood. Using nucl...
| Main Authors: | , , , , , , , , , , |
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| Format: | Article |
| Language: | English |
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Elsevier
2023-01-01
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| Series: | BBA Advances |
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| Online Access: | http://www.sciencedirect.com/science/article/pii/S2667160323000315 |
| _version_ | 1797405282815442944 |
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| author | Vibeke Akkerman Holger A. Scheidt Peter Reinholdt Mohammad Bashawat Maria Szomek Max Lehmann Pablo Wessig Douglas F. Covey Jacob Kongsted Peter Müller Daniel Wüstner |
| author_facet | Vibeke Akkerman Holger A. Scheidt Peter Reinholdt Mohammad Bashawat Maria Szomek Max Lehmann Pablo Wessig Douglas F. Covey Jacob Kongsted Peter Müller Daniel Wüstner |
| author_sort | Vibeke Akkerman |
| collection | DOAJ |
| description | Natamycin is an antifungal polyene macrolide that is used as a food preservative but also to treat fungal keratitis and other yeast infections. In contrast to other polyene antimycotics, natamycin does not form ion pores in the plasma membrane, but its mode of action is poorly understood. Using nuclear magnetic resonance (NMR) spectroscopy of deuterated sterols, we find that natamycin slows the mobility of ergosterol and cholesterol in liquid-ordered (Lo) membranes to a similar extent. This is supported by molecular dynamics (MD) simulations, which additionally reveal a strong impact of natamycin dimers on sterol dynamics and water permeability. Interference with sterol-dependent lipid packing is also reflected in a natamycin-mediated increase in membrane accessibility for dithionite, particularly in bilayers containing ergosterol. NMR experiments with deuterated sphingomyelin (SM) in sterol-containing membranes reveal that natamycin reduces phase separation and increases lipid exchange in bilayers with ergosterol. In ternary lipid mixtures containing monounsaturated phosphatidylcholine, saturated SM, and either ergosterol or cholesterol, natamycin interferes with phase separation into Lo and liquid-disordered (Ld) domains, as shown by NMR spectroscopy. Employing the intrinsic fluorescence of natamycin in ultraviolet-sensitive microscopy, we can visualize the binding of natamycin to giant unilamellar vesicles (GUVs) and find that it has the highest affinity for the Lo phase in GUVs containing ergosterol. Our results suggest that natamycin specifically interacts with the sterol-induced ordered phase, in which it disrupts lipid packing and increases solvent accessibility. This property is particularly pronounced in ergosterol containing membranes, which could underlie the selective antifungal activity of natamycin. |
| first_indexed | 2024-03-09T03:07:35Z |
| format | Article |
| id | doaj.art-041ec6aab4b0418b99b133f0163d9c86 |
| institution | Directory Open Access Journal |
| issn | 2667-1603 |
| language | English |
| last_indexed | 2024-03-09T03:07:35Z |
| publishDate | 2023-01-01 |
| publisher | Elsevier |
| record_format | Article |
| series | BBA Advances |
| spelling | doaj.art-041ec6aab4b0418b99b133f0163d9c862023-12-04T05:24:56ZengElsevierBBA Advances2667-16032023-01-014100102Natamycin interferes with ergosterol-dependent lipid phases in model membranesVibeke Akkerman0Holger A. Scheidt1Peter Reinholdt2Mohammad Bashawat3Maria Szomek4Max Lehmann5Pablo Wessig6Douglas F. Covey7Jacob Kongsted8Peter Müller9Daniel Wüstner10Department of Biochemistry and Molecular Biology, University of Southern Denmark, DK-5230, Odense M, DenmarkInstitute for Medical Physics and Biophysics, Leipzig University, Härtelstr. 16-18, D-04107, Leipzig, GermanyDepartment of Physics, Chemistry and Pharmacy, University of Southern Denmark, DK-5230, Odense M, DenmarkDepartment of Biology, Humboldt University Berlin, Invalidenstr. 43, D-10115, Berlin, GermanyDepartment of Biochemistry and Molecular Biology, University of Southern Denmark, DK-5230, Odense M, DenmarkInstitute for Chemistry, University of Potsdam, Karl-Liebknecht-Str. 24-25, D-14476, Potsdam, GermanyInstitute for Chemistry, University of Potsdam, Karl-Liebknecht-Str. 24-25, D-14476, Potsdam, GermanyDepartment of Developmental Biology, Washington University, St. Louis, MO, 63110, USA; Taylor Family Institute for Innovative Psychiatric Research, St. Louis, Missouri, USADepartment of Physics, Chemistry and Pharmacy, University of Southern Denmark, DK-5230, Odense M, DenmarkDepartment of Biology, Humboldt University Berlin, Invalidenstr. 43, D-10115, Berlin, GermanyDepartment of Biochemistry and Molecular Biology, University of Southern Denmark, DK-5230, Odense M, Denmark; Corresponding author at: Department of Biochemistry and Molecular Biology, University of Southern Denmark, Campusvej 55, DK-5230, Odense M, Denmark.Natamycin is an antifungal polyene macrolide that is used as a food preservative but also to treat fungal keratitis and other yeast infections. In contrast to other polyene antimycotics, natamycin does not form ion pores in the plasma membrane, but its mode of action is poorly understood. Using nuclear magnetic resonance (NMR) spectroscopy of deuterated sterols, we find that natamycin slows the mobility of ergosterol and cholesterol in liquid-ordered (Lo) membranes to a similar extent. This is supported by molecular dynamics (MD) simulations, which additionally reveal a strong impact of natamycin dimers on sterol dynamics and water permeability. Interference with sterol-dependent lipid packing is also reflected in a natamycin-mediated increase in membrane accessibility for dithionite, particularly in bilayers containing ergosterol. NMR experiments with deuterated sphingomyelin (SM) in sterol-containing membranes reveal that natamycin reduces phase separation and increases lipid exchange in bilayers with ergosterol. In ternary lipid mixtures containing monounsaturated phosphatidylcholine, saturated SM, and either ergosterol or cholesterol, natamycin interferes with phase separation into Lo and liquid-disordered (Ld) domains, as shown by NMR spectroscopy. Employing the intrinsic fluorescence of natamycin in ultraviolet-sensitive microscopy, we can visualize the binding of natamycin to giant unilamellar vesicles (GUVs) and find that it has the highest affinity for the Lo phase in GUVs containing ergosterol. Our results suggest that natamycin specifically interacts with the sterol-induced ordered phase, in which it disrupts lipid packing and increases solvent accessibility. This property is particularly pronounced in ergosterol containing membranes, which could underlie the selective antifungal activity of natamycin.http://www.sciencedirect.com/science/article/pii/S2667160323000315Polyene macrolideYeastAntifungalsErgosterolCholesterolLipid phase |
| spellingShingle | Vibeke Akkerman Holger A. Scheidt Peter Reinholdt Mohammad Bashawat Maria Szomek Max Lehmann Pablo Wessig Douglas F. Covey Jacob Kongsted Peter Müller Daniel Wüstner Natamycin interferes with ergosterol-dependent lipid phases in model membranes BBA Advances Polyene macrolide Yeast Antifungals Ergosterol Cholesterol Lipid phase |
| title | Natamycin interferes with ergosterol-dependent lipid phases in model membranes |
| title_full | Natamycin interferes with ergosterol-dependent lipid phases in model membranes |
| title_fullStr | Natamycin interferes with ergosterol-dependent lipid phases in model membranes |
| title_full_unstemmed | Natamycin interferes with ergosterol-dependent lipid phases in model membranes |
| title_short | Natamycin interferes with ergosterol-dependent lipid phases in model membranes |
| title_sort | natamycin interferes with ergosterol dependent lipid phases in model membranes |
| topic | Polyene macrolide Yeast Antifungals Ergosterol Cholesterol Lipid phase |
| url | http://www.sciencedirect.com/science/article/pii/S2667160323000315 |
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