Crowdsourcing natural products discovery to access uncharted dimensions of fungal metabolite diversity

A fundamental component for success in drug discovery is the ability to assemble and screen compounds that encompass a broad swath of biologically relevant chemical-diversity space. Achieving this goal in a natural-products- based setting requires access to a wide range of biologically diverse specimens. For this reason, we introduced a crowdsourcing program in which citizen scientists furnish soil samples from which new microbial isolates are procured. Illustrating the strength of this approach, we obtained a unique fungal metabolite, maximiscin, from a crowdsourced Alaskan soil sample. Maximiscin, which exhibits a putative combination of polyketide synthase (PKS), non-ribosomal peptide synthetase (NRPS), and shikimate pathway components, was identified as an inhibitor of UACC-62 melanoma cells (LC50=0.93 μM). The metabolite also exhibited efficacy in a xenograft mouse model. These results underscore the value of building cooperative relationships between research teams and citizen scientists to enrich drug discovery efforts. A fungus among us: A new Tolypocladium sp. was obtained through a crowdsourcing initiative. The expression of a silent biosynthetic pathway in this fungus was triggered through chemical epigenetics, culture medium manipulation, and co-culture to yield the unique polyketide-shikimate-NRPS-hybrid compound, maximiscin, which demonstrated in vivo antitumor activity. NRPS=non-ribosomal peptide synthetase.