title: Marine antifungal theonellamides target 3beta-hydroxysterol to activate Rho1 signaling.
abstract: Linking bioactive compounds to their cellular targets is a central challenge in chemical biology. Here we report the mode of action of theonellamides, bicyclic peptides derived from marine sponges. We generated a chemical-genomic profile of theonellamide F using a collection of fission yeast strains in which each open reading frame (ORF) is expressed under the control of an inducible promoter. Clustering analysis of the Gene Ontology (GO) terms associated with the genes that alter drug sensitivity suggested a mechanistic link between theonellamide and 1,3-beta-D-glucan synthesis. Indeed, theonellamide F induced overproduction of 1,3-beta-D-glucan in a Rho1-dependent manner. Subcellular localization and in vitro binding assays using a fluorescent theonellamide derivative revealed that theonellamides specifically bind to 3beta-hydroxysterols, including ergosterol, and cause membrane damage. The biological activity of theonellamides was alleviated in mutants defective in ergosterol biosynthesis. Theonellamides thus represent a new class of sterol-binding molecules that induce membrane damage and activate Rho1-mediated 1,3-beta-D-glucan synthesis.
authors.affiliation: Chemical Genomics Research Group, RIKEN Advanced Science Institute, Saitama, Japan.
authors.forename: Shinichi
authors.initials: S
authors.lastname: Nishimura
authors.forename: Yuko
authors.initials: Y
authors.lastname: Arita
authors.forename: Miyuki
authors.initials: M
authors.lastname: Honda
authors.forename: Kunihiko
authors.initials: K
authors.lastname: Iwamoto
authors.forename: Akihisa
authors.initials: A
authors.lastname: Matsuyama
authors.forename: Atsuko
authors.initials: A
authors.lastname: Shirai
authors.forename: Hisashi
authors.initials: H
authors.lastname: Kawasaki
authors.forename: Hideaki
authors.initials: H
authors.lastname: Kakeya
authors.forename: Toshihide
authors.initials: T
authors.lastname: Kobayashi
authors.forename: Shigeki
authors.initials: S
authors.lastname: Matsunaga
authors.forename: Minoru
authors.initials: M
authors.lastname: Yoshida
mesh_terms: D000818:Animals; D000935:Antifungal Agents / Q000737:chemistry* / Q000494:pharmacology*; D004353:Drug Evaluation, Preclinical; D054714:Echinocandins / Q000494:pharmacology; D020869:Gene Expression Profiling; D006914:Hydroxysteroids / Q000378:metabolism*; D055666:Lipopeptides / Q000494:pharmacology; D008386:Marine Biology; D000077551:Micafungin; D015394:Molecular Structure; D010456:Peptides, Cyclic / Q000494:pharmacology*; D012568:Schizosaccharomyces / Q000166:cytology / Q000187:drug effects; D029702:Schizosaccharomyces pombe Proteins / Q000378:metabolism*; D047232:Theonella / Q000737:chemistry; D020741:rho GTP-Binding Proteins / Q000378:metabolism*
chemical_list: D000935:Antifungal Agents; D054714:Echinocandins; D006914:Hydroxysteroids; D055666:Lipopeptides; D010456:Peptides, Cyclic; D029702:Schizosaccharomyces pombe Proteins; C550807:theonellamide F; D020741:rho GTP-Binding Proteins; C511156:rho1 protein, S pombe; D000077551:Micafungin