title: Crowdsourcing natural products discovery to access uncharted dimensions of fungal metabolite diversity.
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.
authors.affiliation: Department of Chemistry and Biochemistry, Stephenson Life Sciences Research Center, University of Oklahoma, 101 Stephenson Parkway Norman, OK 73019-5251 (USA); Natural Products Discovery Group and Institute for Natural Products Applications and Research Technologies, University of Oklahoma (USA).
authors.forename: Lin
authors.initials: L
authors.lastname: Du
authors.forename: Andrew J
authors.initials: AJ
authors.lastname: Robles
authors.forename: Jarrod B
authors.initials: JB
authors.lastname: King
authors.forename: Douglas R
authors.initials: DR
authors.lastname: Powell
authors.forename: Andrew N
authors.initials: AN
authors.lastname: Miller
authors.forename: Susan L
authors.initials: SL
authors.lastname: Mooberry
authors.forename: Robert H
authors.initials: RH
authors.lastname: Cichewicz
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000378:metabolism* / Q000627:therapeutic use / Q000633:toxicity; D001688:Biological Products / Q000378:metabolism* / Q000627:therapeutic use / Q000633:toxicity; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects; D018920:Coculture Techniques; D018360:Crystallography, X-Ray; D004353:Drug Evaluation, Preclinical; D005658:Fungi / Q000378:metabolism*; D006801:Humans; D008545:Melanoma / Q000188:drug therapy; D008715:Methionine / Q000737:chemistry / Q000378:metabolism* / Q000633:toxicity; D051379:Mice; D008968:Molecular Conformation; D010453:Peptide Synthases / Q000378:metabolism; D061065:Polyketides / Q000737:chemistry / Q000378:metabolism; D011549:Pseudomonas / Q000378:metabolism; D012765:Shikimic Acid / Q000737:chemistry / Q000378:metabolism; D014183:Transplantation, Heterologous; D014443:Tyrosine / Q000737:chemistry / Q000378:metabolism* / Q000633:toxicity
chemical_list: D000970:Antineoplastic Agents; D001688:Biological Products; D061065:Polyketides; D012765:Shikimic Acid; D014443:Tyrosine; D008715:Methionine; D010453:Peptide Synthases; C104385:non-ribosomal peptide synthase
keywords: antitumor agents; biosynthesis; crowdsourcing; drug discovery; epigenetics