title: Hassallidins, antifungal glycolipopeptides, are widespread among cyanobacteria and are the end-product of a nonribosomal pathway.
abstract: Cyanobacteria produce a wide variety of cyclic peptides, including the widespread hepatotoxins microcystins and nodularins. Another class of peptides, cyclic glycosylated lipopeptides called hassallidins, show antifungal activity. Previously, two hassallidins (A and B) were reported from an epilithic cyanobacterium Hassallia sp. and found to be active against opportunistic human pathogenic fungi. Bioinformatic analysis of the Anabaena sp. 90 genome identified a 59-kb cryptic inactive nonribosomal peptide synthetase gene cluster proposed to be responsible for hassallidin biosynthesis. Here we describe the hassallidin biosynthetic pathway from Anabaena sp. SYKE748A, as well as the large chemical variation and common occurrence of hassallidins in filamentous cyanobacteria. Analysis demonstrated that 20 strains of the genus Anabaena carry hassallidin synthetase genes and produce a multitude of hassallidin variants that exhibit activity against Candida albicans. The compounds discovered here were distinct from previously reported hassallidins A and B. The IC50 of hassallidin D was 0.29-1.0 µM against Candida strains. A large variation in amino acids, sugars, their degree of acetylation, and fatty acid side chain length was detected. In addition, hassallidins were detected in other cyanobacteria including Aphanizomenon, Cylindrospermopsis raciborskii, Nostoc, and Tolypothrix. These compounds may protect some of the most important bloom-forming and globally distributed cyanobacteria against attacks by parasitic fungi.
authors.affiliation: Department of Food and Environmental Sciences, Viikki Biocenter 1, University of Helsinki, FI-00014, Helsinki, Finland.
authors.forename: Johanna
authors.initials: J
authors.lastname: Vestola
authors.forename: Tania K
authors.initials: TK
authors.lastname: Shishido
authors.forename: Jouni
authors.initials: J
authors.lastname: Jokela
authors.forename: David P
authors.initials: DP
authors.lastname: Fewer
authors.forename: Olli
authors.initials: O
authors.lastname: Aitio
authors.forename: Perttu
authors.initials: P
authors.lastname: Permi
authors.forename: Matti
authors.initials: M
authors.lastname: Wahlsten
authors.forename: Hao
authors.initials: H
authors.lastname: Wang
authors.forename: Leo
authors.initials: L
authors.lastname: Rouhiainen
authors.forename: Kaarina
authors.initials: K
authors.lastname: Sivonen
mesh_terms: D017033:Anabaena / Q000235:genetics / Q000378:metabolism*; D000935:Antifungal Agents / Q000737:chemistry / Q000378:metabolism* / Q000494:pharmacology; D002176:Candida albicans / Q000187:drug effects; D000458:Cyanobacteria / Q000235:genetics / Q000378:metabolism*; D005798:Genes, Bacterial; D006017:Glycolipids / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D006020:Glycopeptides / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D055666:Lipopeptides / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D053858:Metabolic Networks and Pathways; D008969:Molecular Sequence Data; D015394:Molecular Structure; D005810:Multigene Family; D019906:Nuclear Magnetic Resonance, Biomolecular; D010456:Peptides, Cyclic / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D010802:Phylogeny
chemical_list: D000935:Antifungal Agents; D006017:Glycolipids; D006020:Glycopeptides; D055666:Lipopeptides; D010456:Peptides, Cyclic; C501712:hassallidin A; C513949:hassallidin B; C000589199:hassallidin C; C000589200:hassallidin D
keywords: bioactive peptide; genome mining; natural product discovery; nonribosomal peptide synthesis; secondary metabolites
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