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

6533b7d2fe1ef96bd125f527

RESEARCH PRODUCT

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

Jouni Jokela Anu Humisto Knut Teigen Perttu Permi Kaarina Sivonen Lars Herfindal Matti Wahlsten

subject

Antifungal Agents kolesteroli Peptide Lipopeptide 01 natural sciences Biochemistry chemistry.chemical_compound STRUCTURE ELUCIDATION Candida albicans MARINE CYANOBACTERIA mammalian cells membrane 1183 Plant biology microbiology virology chemistry.chemical_classification 0303 health sciences Cell Death Membrane Glycopeptides Lipopeptide HERBICOLIN-A DEHYDROPEPTIDE LACTONE Amino acid Sterols Cholesterol Membrane Biochemistry solunsalpaajat Mitochondrial Membranes medicine.symptom Bacterial outer membrane Biophysics mechanism Antineoplastic Agents saponin digitonin Molecular dynamics Cyanobacteria ITURIN-A 03 medical and health sciences Lipopeptides Membrane Lipids NATURAL-PRODUCTS Cell Line Tumor medicine Humans Propidium iodide syanobakteerit 030304 developmental biology antimikrobiset yhdisteet 010405 organic chemistry MAJOR COMPONENT Cell Biology luonnonaineet Anabaena Sterol 0104 chemical sciences Mechanism of action chemistry lipopeptide peptidit MOLECULAR-DYNAMICS 1182 Biochemistry cell and molecular biology Drug Screening Assays Antitumor Glycolipids

description

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. publishedVersion

year	journal	country	edition	language
2019-08-01	Biochimica et biophysica acta. Biomembranes

10.1016/j.bbamem.2019.03.010 https://pubmed.ncbi.nlm.nih.gov/31226245