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Characterization of the interaction of the antifungal and cytotoxic cyclic glycolipopeptide hassallidin with sterol-containing lipid membranes.

Authors
  • Humisto, Anu1
  • Jokela, Jouni1
  • Teigen, Knut2
  • Wahlsten, Matti1
  • Permi, Perttu3
  • Sivonen, Kaarina1
  • Herfindal, Lars4
  • 1 Department of Microbiology, University of Helsinki, Viikki Biocenter 1, P.O. Box 56, FI-00014 Helsinki, Finland. , (Finland)
  • 2 Centre for Pharmacy, Department of Biomedicine, University of Bergen, N-5009 Bergen, Norway. , (Norway)
  • 3 Department of Biological and Environmental Science, University of Jyvaskyla, P.O Box 35, FI-40014 Jyvaskyla, Finland; Department of Chemistry, Nanoscience Center, University of Jyvaskyla, P.O Box 35, FI-40014 Jyvaskyla, Finland. , (Finland)
  • 4 Centre for Pharmacy, Department of Clinical Science, University of Bergen, N-5009 Bergen, Norway. Electronic address: [email protected] , (Norway)
Type
Published Article
Journal
Biochimica et biophysica acta. Biomembranes
Publication Date
Aug 01, 2019
Volume
1861
Issue
8
Pages
1510–1521
Identifiers
DOI: 10.1016/j.bbamem.2019.03.010
PMID: 31226245
Source
Medline
Keywords
Language
English
License
Unknown

Abstract

Hassallidins are cyclic glycolipopeptides produced by cyanobacteria and other prokaryotes. The hassallidin structure consists of a peptide ring of eight amino acids where a fatty acid chain, additional amino acids, and sugar moieties are attached. Hassallidins show antifungal activity against several opportunistic human pathogenic fungi, but does not harbor antibacterial effects. However, they have not been studied on mammalian cells, and the mechanism of action is unknown. We purified hassallidin D from cultured cyanobacterium Anabaena sp. UHCC 0258 and characterized its effect on mammalian and fungal cells. Ultrastructural analysis showed that hassallidin D disrupts cell membranes, causing a lytic/necrotic cell death with rapid presence of disintegrated outer membrane, accompanied by internalization of small molecules such as propidium iodide into the cells. Furthermore, artificial liposomal membrane assay showed that hassallidin D selectively targets sterol-containing membranes. Finally, in silico membrane modeling allowed us to study the interaction between hassallidin D and membranes in detail, and confirm the role of cholesterol for hassallidin-insertion into the membrane. This study demonstrates the mechanism of action of the natural compound hassallidin, and gives further insight into how bioactive lipopeptide metabolites selectively target eukaryotic cell membranes. Copyright © 2019 The Author(s). Published by Elsevier B.V. All rights reserved.

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