title: Cytotoxic and antifungal activities of melleolide antibiotics follow dissimilar structure-activity relationships.
abstract: The fungal genus Armillaria is unique in that it is the only natural source of melleolide antibiotics, i.e., protoilludene alcohols esterified with orsellinic acid or its derivatives. This class of natural products is known to exert antimicrobial and cytotoxic effects. Here, we present a refined relationship between the structure and the antimicrobial activity of the melleolides. Using both agar diffusion and broth dilution assays, we identified the Δ(2,4)-double bond of the protoilludene moiety as a key structural feature for antifungal activity against Aspergillus nidulans, Aspergillus flavus, and Penicillium notatum. These findings contrast former reports on cytotoxic activities and may indicate a different mode of action towards susceptible fungi. We also report the isolation and structure elucidation of five melleolides (6'-dechloroarnamial, 6'-chloromelleolide F, 10-hydroxy-5'-methoxy-6'-chloroarmillane, and 13-deoxyarmellides A and B), along with the finding that treatment with an antifungal melleolide impacts transcription of A. nidulans natural product genes.
authors.affiliation: Department Pharmaceutical Biology at the Hans-Knöll-Institute, Friedrich-Schiller-Universität Jena, Beutenbergstrasse 11a, 07745 Jena, Germany. Electronic address: markus.bohnert@hki-jena.de.
authors.forename: Markus
authors.initials: M
authors.lastname: Bohnert
authors.affiliation: Department Molecular and Applied Microbiology, Leibniz-Institute for Infection Biology and Natural Product Research - Hans-Knöll-Institute, Beutenbergstrasse 11a, 07745 Jena, Germany. Electronic address: hans-wilhelm.nutzmann@jic.ac.uk.
authors.forename: Hans-Wilhelm
authors.initials: HW
authors.lastname: Nützmann
authors.affiliation: Department Molecular and Applied Microbiology, Leibniz-Institute for Infection Biology and Natural Product Research - Hans-Knöll-Institute, Beutenbergstrasse 11a, 07745 Jena, Germany. Electronic address: volker.schroeckh@hki-jena.de.
authors.forename: Volker
authors.initials: V
authors.lastname: Schroeckh
authors.affiliation: Department Systems Biology and Bioinformatics, Leibniz-Institute for Infection Biology and Natural Product Research - Hans-Knöll-Institute, Beutenbergstrasse 11a, 07745 Jena, Germany. Electronic address: fabian.horn@hki-jena.de.
authors.forename: Fabian
authors.initials: F
authors.lastname: Horn
authors.affiliation: Department Infection Biology, Leibniz-Institute for Infection Biology and Natural Product Research - Hans-Knöll-Institute, Beutenbergstrasse 11a, 07745 Jena, Germany. Electronic address: hans-martin.dahse@hki-jena.de.
authors.forename: Hans-Martin
authors.initials: HM
authors.lastname: Dahse
authors.affiliation: Department Molecular and Applied Microbiology, Leibniz-Institute for Infection Biology and Natural Product Research - Hans-Knöll-Institute, Beutenbergstrasse 11a, 07745 Jena, Germany. Electronic address: axel.brakhage@hki-jena.de.
authors.forename: Axel A
authors.initials: AA
authors.lastname: Brakhage
authors.affiliation: Department Pharmaceutical Biology at the Hans-Knöll-Institute, Friedrich-Schiller-Universität Jena, Beutenbergstrasse 11a, 07745 Jena, Germany. Electronic address: dirk.hoffmeister@hki-jena.de.
authors.forename: Dirk
authors.initials: D
authors.lastname: Hoffmeister
mesh_terms: D000900:Anti-Bacterial Agents / Q000737:chemistry / Q000302:isolation & purification* / Q000494:pharmacology*; D000890:Anti-Infective Agents / Q000737:chemistry / Q000302:isolation & purification* / Q000494:pharmacology*; D000935:Antifungal Agents / Q000737:chemistry / Q000302:isolation & purification* / Q000494:pharmacology*; D055392:Armillaria / Q000737:chemistry*; D001230:Aspergillus / Q000187:drug effects; D005658:Fungi / Q000187:drug effects; D015394:Molecular Structure; D019906:Nuclear Magnetic Resonance, Biomolecular; D012118:Resorcinols; D012717:Sesquiterpenes / Q000737:chemistry / Q000302:isolation & purification* / Q000494:pharmacology*; D013329:Structure-Activity Relationship
chemical_list: D000900:Anti-Bacterial Agents; D000890:Anti-Infective Agents; D000935:Antifungal Agents; D012118:Resorcinols; D012717:Sesquiterpenes; C501612:orsellinic acid
keywords: Armillaria mellea; Melleolide; Natural product characterization; Physalacriaceae; Sesquiterpene aryl ester; Structure–activity relationship