title: Plant-derived antifungal agent poacic acid targets β-1,3-glucan.
abstract: A rise in resistance to current antifungals necessitates strategies to identify alternative sources of effective fungicides. We report the discovery of poacic acid, a potent antifungal compound found in lignocellulosic hydrolysates of grasses. Chemical genomics using Saccharomyces cerevisiae showed that loss of cell wall synthesis and maintenance genes conferred increased sensitivity to poacic acid. Morphological analysis revealed that cells treated with poacic acid behaved similarly to cells treated with other cell wall-targeting drugs and mutants with deletions in genes involved in processes related to cell wall biogenesis. Poacic acid causes rapid cell lysis and is synergistic with caspofungin and fluconazole. The cellular target was identified; poacic acid localized to the cell wall and inhibited β-1,3-glucan synthesis in vivo and in vitro, apparently by directly binding β-1,3-glucan. Through its activity on the glucan layer, poacic acid inhibits growth of the fungi Sclerotinia sclerotiorum and Alternaria solani as well as the oomycete Phytophthora sojae. A single application of poacic acid to leaves infected with the broad-range fungal pathogen S. sclerotiorum substantially reduced lesion development. The discovery of poacic acid as a natural antifungal agent targeting β-1,3-glucan highlights the potential side use of products generated in the processing of renewable biomass toward biofuels as a source of valuable bioactive compounds and further clarifies the nature and mechanism of fermentation inhibitors found in lignocellulosic hydrolysates.
authors.affiliation: Great Lakes Bioenergy Research Center, University of Wisconsin-Madison, Madison, WI 53703; jpiotrowski@wisc.edu ohya@k.u-tokyo.ac.jp.
authors.forename: Jeff S
authors.initials: JS
authors.lastname: Piotrowski
authors.affiliation: Department of Integrated Biosciences, Graduate School of Frontier Sciences, University of Tokyo, Kashiwa, Chiba, Japan 277-8561;
authors.forename: Hiroki
authors.initials: H
authors.lastname: Okada
authors.affiliation: Great Lakes Bioenergy Research Center, University of Wisconsin-Madison, Madison, WI 53703;
authors.forename: Fachuang
authors.initials: F
authors.lastname: Lu
authors.affiliation: RIKEN Center for Sustainable Resource Science, Wako, Saitama, Japan 351-0198;
authors.forename: Sheena C
authors.initials: SC
authors.lastname: Li
authors.affiliation: Great Lakes Bioenergy Research Center, University of Wisconsin-Madison, Madison, WI 53703;
authors.forename: Li
authors.initials: L
authors.lastname: Hinchman
authors.affiliation: Departments of Plant Pathology and.
authors.forename: Ashish
authors.initials: A
authors.lastname: Ranjan
authors.affiliation: Departments of Plant Pathology and.
authors.forename: Damon L
authors.initials: DL
authors.lastname: Smith
authors.affiliation: Chemistry, University of Wisconsin-Madison, Madison, WI 53706;
authors.forename: Alan J
authors.initials: AJ
authors.lastname: Higbee
authors.affiliation: Chemistry, University of Wisconsin-Madison, Madison, WI 53706;
authors.forename: Arne
authors.initials: A
authors.lastname: Ulbrich
authors.affiliation: Chemistry, University of Wisconsin-Madison, Madison, WI 53706;
authors.forename: Joshua J
authors.initials: JJ
authors.lastname: Coon
authors.affiliation: Department of Computer Science and Engineering, University of Minnesota-Twin Cities, Minneapolis, MN 55455; and.
authors.forename: Raamesh
authors.initials: R
authors.lastname: Deshpande
authors.affiliation: Great Lakes Bioenergy Research Center, University of Wisconsin-Madison, Madison, WI 53703;
authors.forename: Yury V
authors.initials: YV
authors.lastname: Bukhman
authors.affiliation: Great Lakes Bioenergy Research Center, University of Wisconsin-Madison, Madison, WI 53703;
authors.forename: Sean
authors.initials: S
authors.lastname: McIlwain
authors.affiliation: Great Lakes Bioenergy Research Center, University of Wisconsin-Madison, Madison, WI 53703;
authors.forename: Irene M
authors.initials: IM
authors.lastname: Ong
authors.affiliation: Department of Computer Science and Engineering, University of Minnesota-Twin Cities, Minneapolis, MN 55455; and.
authors.forename: Chad L
authors.initials: CL
authors.lastname: Myers
authors.affiliation: RIKEN Center for Sustainable Resource Science, Wako, Saitama, Japan 351-0198; Terrence Donnelly Centre for Cellular and Biomolecular Research, University of Toronto, Toronto, ON, Canada M5S 3E1.
authors.forename: Charles
authors.initials: C
authors.lastname: Boone
authors.affiliation: Great Lakes Bioenergy Research Center, University of Wisconsin-Madison, Madison, WI 53703;
authors.forename: Robert
authors.initials: R
authors.lastname: Landick
authors.affiliation: Great Lakes Bioenergy Research Center, University of Wisconsin-Madison, Madison, WI 53703;
authors.forename: John
authors.initials: J
authors.lastname: Ralph
authors.affiliation: Departments of Plant Pathology and.
authors.forename: Mehdi
authors.initials: M
authors.lastname: Kabbage
authors.affiliation: Department of Integrated Biosciences, Graduate School of Frontier Sciences, University of Tokyo, Kashiwa, Chiba, Japan 277-8561; jpiotrowski@wisc.edu ohya@k.u-tokyo.ac.jp.
authors.forename: Yoshikazu
authors.initials: Y
authors.lastname: Ohya
mesh_terms: D000077336:Caspofungin; D002462:Cell Membrane / Q000378:metabolism; D002473:Cell Wall / Q000378:metabolism; D003373:Coumaric Acids / Q000737:chemistry*; D004305:Dose-Response Relationship, Drug; D004357:Drug Synergism; D054714:Echinocandins / Q000737:chemistry; D005659:Fungicides, Industrial / Q000737:chemistry*; D023281:Genomics; D006868:Hydrolysis; D020128:Inhibitory Concentration 50; D008031:Lignin / Q000737:chemistry; D055666:Lipopeptides; D010936:Plant Extracts / Q000737:chemistry; D006109:Poaceae / Q000737:chemistry*; D012441:Saccharomyces cerevisiae / Q000187:drug effects* / Q000378:metabolism; D013267:Stilbenes / Q000737:chemistry*; D047071:beta-Glucans / Q000737:chemistry*
chemical_list: D003373:Coumaric Acids; D054714:Echinocandins; D005659:Fungicides, Industrial; D055666:Lipopeptides; D010936:Plant Extracts; D013267:Stilbenes; D047071:beta-Glucans; C000598562:poacic acid; C036909:lignocellulose; D008031:Lignin; C033363:beta-1,3-glucan; D000077336:Caspofungin
keywords: Saccharomyces cerevisiae; chemical genomics; fungal cell wall; high-dimensional morphometrics; lignocellulosic hydrolysates