title: Antifungal activity improved by coproduction of cyclodextrins and anabaenolysins in Cyanobacteria.
abstract: Cyclodextrins are cyclic oligosaccharides widely used in the pharmaceutical industry to improve drug delivery and to increase the solubility of hydrophobic compounds. Anabaenolysins are lipopeptides produced by cyanobacteria with potent lytic activity in cholesterol-containing membranes. Here, we identified the 23- to 24-kb gene clusters responsible for the production of the lipopeptide anabaenolysin. The hybrid nonribosomal peptide synthetase and polyketide synthase biosynthetic gene cluster is encoded in the genomes of three anabaenolysin-producing strains of Anabaena. We detected previously unidentified strains producing known anabaenolysins A and B and discovered the production of new variants of anabaenolysins C and D. Bioassays demonstrated that anabaenolysins have weak antifungal activity against Candida albicans. Surprisingly, addition of the hydrophilic fraction of the whole-cell extracts increased the antifungal activity of the hydrophobic anabaenolysins. The fraction contained compounds identified by NMR as α-, β-, and γ-cyclodextrins, which undergo acetylation. Cyclodextrins have been used for decades to improve the solubility and bioavailability of many drugs including antifungal compounds. This study shows a natural example of cyclodextrins improving the solubility and efficacy of an antifungal compound in an ancient lineage of photosynthetic bacteria.
authors.affiliation: Department of Food and Environmental Sciences, University of Helsinki, FI-00014, Helsinki, Finland;
authors.forename: Tania K
authors.initials: TK
authors.lastname: Shishido
authors.affiliation: Department of Food and Environmental Sciences, University of Helsinki, FI-00014, Helsinki, Finland;
authors.forename: Jouni
authors.initials: J
authors.lastname: Jokela
authors.affiliation: Department of Food and Environmental Sciences, University of Helsinki, FI-00014, Helsinki, Finland;
authors.forename: Clara-Theresia
authors.initials: CT
authors.lastname: Kolehmainen
authors.affiliation: Department of Food and Environmental Sciences, University of Helsinki, FI-00014, Helsinki, Finland;
authors.forename: David P
authors.initials: DP
authors.lastname: Fewer
authors.affiliation: Department of Food and Environmental Sciences, University of Helsinki, FI-00014, Helsinki, Finland;
authors.forename: Matti
authors.initials: M
authors.lastname: Wahlsten
authors.affiliation: Department of Food and Environmental Sciences, University of Helsinki, FI-00014, Helsinki, Finland;
authors.forename: Hao
authors.initials: H
authors.lastname: Wang
authors.affiliation: Department of Food and Environmental Sciences, University of Helsinki, FI-00014, Helsinki, Finland;
authors.forename: Leo
authors.initials: L
authors.lastname: Rouhiainen
authors.affiliation: Institute of Biomedical Technologies, National Research Council, 20090, Segrate, Milan, Italy;
authors.forename: Ermanno
authors.initials: E
authors.lastname: Rizzi
authors.affiliation: Institute of Biomedical Technologies, National Research Council, 20090, Segrate, Milan, Italy;
authors.forename: Gianluca
authors.initials: G
authors.lastname: De Bellis
authors.affiliation: Program in Structural Biology and Biophysics, Institute of Biotechnology/Nuclear Magnetic Resonance Laboratory, University of Helsinki, FI-00014, Helsinki, Finland; Department of Biological and Environmental Science, Nanoscience Center, University of Jyväskylä, FI-40014, Jyväskylä, Finland; Department of Chemistry, Nanoscience Center, University of Jyväskylä, FI-40014, Jyväskylä, Finland.
authors.forename: Perttu
authors.initials: P
authors.lastname: Permi
authors.affiliation: Department of Food and Environmental Sciences, University of Helsinki, FI-00014, Helsinki, Finland; kaarina.sivonen@helsinki.fi.
authors.forename: Kaarina
authors.initials: K
authors.lastname: Sivonen
mesh_terms: D000935:Antifungal Agents / Q000494:pharmacology*; D001426:Bacterial Proteins / Q000096:biosynthesis*; D000458:Cyanobacteria / Q000235:genetics / Q000378:metabolism*; D003505:Cyclodextrins / Q000096:biosynthesis*; D005798:Genes, Bacterial; D008969:Molecular Sequence Data
chemical_list: D000935:Antifungal Agents; D001426:Bacterial Proteins; D003505:Cyclodextrins
keywords: NRPS; PKS; bioactive compounds; hydroxyamino fatty acid; natural products