Elucidation of the mangicol and neomangicol biosynthetic pathway from the marine fungus Fusarium equiseti CNC-477

Abstract

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 feasible resources for drug discovery programs. The marine-derived fungal strain Fusarium equiseti CNC-477, characterized by the Fenical laboratory, was 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 crucial for bioactivity. De novo genome sequencing and assembly has revealed candidate biosynthetic clusters responsible for the synthesis of these sesterterpene polyols. These biosynthetic clusters, a proposed biosynthetic route and the development of alternative platforms for the heterologous production of the mangicols and neomangicols will be presented.