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Ergosterol promotes aggregation of natamycin in the yeast plasma membrane.
Szomek, Maria; Akkerman, Vibeke; Lauritsen, Line; Walther, Hanna-Loisa; Juhl, Alice Dupont; Thaysen, Katja; Egebjerg, Jacob Marcus; Covey, Douglas F; Lehmann, Max; Wessig, Pablo; Foster, Alexander J; Poolman, Bert; Werner, Stephan; Schneider, Gerd; Müller, Peter; Wüstner, Daniel.
Afiliación
  • Szomek M; Department of Biochemistry and Molecular Biology, University of Southern Denmark, DK-5230 Odense M, Denmark.
  • Akkerman V; Department of Biochemistry and Molecular Biology, University of Southern Denmark, DK-5230 Odense M, Denmark.
  • Lauritsen L; Department of Biochemistry and Molecular Biology, University of Southern Denmark, DK-5230 Odense M, Denmark.
  • Walther HL; Department of Biochemistry and Molecular Biology, University of Southern Denmark, DK-5230 Odense M, Denmark.
  • Juhl AD; Department of Biochemistry and Molecular Biology, University of Southern Denmark, DK-5230 Odense M, Denmark.
  • Thaysen K; Department of Biochemistry and Molecular Biology, University of Southern Denmark, DK-5230 Odense M, Denmark.
  • Egebjerg JM; Department of Biochemistry and Molecular Biology, University of Southern Denmark, DK-5230 Odense M, Denmark.
  • Covey DF; Department of Developmental Biology, Washington University in St. Louis, St. Louis, MO 63110, USA; Taylor Family Institute for Innovative Psychiatric Research, USA.
  • Lehmann M; Institute for Chemistry, University of Potsdam, Karl-Liebknecht-Str. 24-25, D-14476 Potsdam, Germany.
  • Wessig P; Institute for Chemistry, University of Potsdam, Karl-Liebknecht-Str. 24-25, D-14476 Potsdam, Germany.
  • Foster AJ; Department of Biochemistry, University of Groningen, Nijenborgh 4, 9747 Groningen, the Netherlands.
  • Poolman B; Department of Biochemistry, University of Groningen, Nijenborgh 4, 9747 Groningen, the Netherlands.
  • Werner S; Department of X-Ray Microscopy, Helmholtz-Zentrum Berlin, Albert-Einstein-Str. 15, 12489 Berlin, Germany.
  • Schneider G; Department of X-Ray Microscopy, Helmholtz-Zentrum Berlin, Albert-Einstein-Str. 15, 12489 Berlin, Germany.
  • Müller P; Department of Biology, Humboldt University Berlin, Invalidenstr. 43, D-10115 Berlin, Germany.
  • Wüstner D; Department of Biochemistry and Molecular Biology, University of Southern Denmark, DK-5230 Odense M, Denmark. Electronic address: wuestner@bmb.sdu.dk.
Biochim Biophys Acta Biomembr ; 1866(7): 184350, 2024 Oct.
Article en En | MEDLINE | ID: mdl-38806103
ABSTRACT
Polyene macrolides are antifungal substances, which interact with cells in a sterol-dependent manner. While being widely used, their mode of action is poorly understood. Here, we employ ultraviolet-sensitive (UV) microscopy to show that the antifungal polyene natamycin binds to the yeast plasma membrane (PM) and causes permeation of propidium iodide into cells. Right before membrane permeability became compromised, we observed clustering of natamycin in the PM that was independent of PM protein domains. Aggregation of natamycin was paralleled by cell deformation and membrane blebbing as revealed by soft X-ray microscopy. Substituting ergosterol for cholesterol decreased natamycin binding and caused a reduced clustering of natamycin in the PM. Blocking of ergosterol synthesis necessitates sterol import via the ABC transporters Aus1/Pdr11 to ensure natamycin binding. Quantitative imaging of dehydroergosterol (DHE) and cholestatrienol (CTL), two analogues of ergosterol and cholesterol, respectively, revealed a largely homogeneous lateral sterol distribution in the PM, ruling out that natamycin binds to pre-assembled sterol domains. Depletion of sphingolipids using myriocin increased natamycin binding to yeast cells, likely by increasing the ergosterol fraction in the outer PM leaflet. Importantly, binding and membrane aggregation of natamycin was paralleled by a decrease of the dipole potential in the PM, and this effect was enhanced in the presence of myriocin. We conclude that ergosterol promotes binding and aggregation of natamycin in the yeast PM, which can be synergistically enhanced by inhibitors of sphingolipid synthesis.
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Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Saccharomyces cerevisiae / Membrana Celular / Natamicina / Proteínas de Saccharomyces cerevisiae / Ergosterol / Antifúngicos Idioma: En Revista: Biochim Biophys Acta Biomembr Año: 2024 Tipo del documento: Article País de afiliación: Dinamarca Pais de publicación: Países Bajos
Texto completo
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Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Saccharomyces cerevisiae / Membrana Celular / Natamicina / Proteínas de Saccharomyces cerevisiae / Ergosterol / Antifúngicos Idioma: En Revista: Biochim Biophys Acta Biomembr Año: 2024 Tipo del documento: Article País de afiliación: Dinamarca Pais de publicación: Países Bajos