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

Lin Du, Andrew J. Robles, Jarrod B. King, Douglas R. Powell, Andrew N. Miller, Susan L. Mooberry, Robert H. Cichewicz

Research output: Contribution to journalArticle

Abstract

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.

Original languageEnglish (US)
Pages (from-to)804-809
Number of pages6
JournalAngewandte Chemie - International Edition
Volume53
Issue number3
DOIs
StatePublished - 2014

Keywords

  • antitumor agents
  • biosynthesis
  • crowdsourcing
  • drug discovery
  • epigenetics

ASJC Scopus subject areas

  • Catalysis
  • Chemistry(all)

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