While actinomycetes are often regarded as good resources for the discovery of bioactive metabolites, the recent explosion in whole genome sequencing has brought filamentous fungi back into the spotlight as novel resources for drug discovery programs. The marine-derived fungal strain Fusarium equiseti CNC-477 was characterized by the Fenical laboratory and shown to be a prolific producer of rare sesterterpene (C25) polyols. Mangicols A–G contain an unprecedented spirotricyclic core and possess remarkable anti-inflammatory activity, whereas neomangicols A–C contain a tetracyclic skeleton and exhibit antimicrobial activities. Both classes of molecules contain multiple hydroxylations on the uncyclized prenyl chain and neomangicols A and B contain an additional chlorine or bromine atom, respectively, that is critical for bioactivity. Following de novo genome sequencing and assembly, genome mining was used to identify the biosynthetic cluster responsible for the synthesis of these sesterterpene polyols. Heterologous expression of the corresponding sesterterpene synthase allowed for the characterization of the cyclopent[e]-s-indacene ring formation observed in the mangicols. The biosynthetic cluster, development of an alternative platform for the heterologous production of terpenes, and characterization of the mangicol sesterterpene synthase will be presented.
