title: Valproic Acid Induces Antimicrobial Compound Production in Doratomyces microspores.
abstract: One of the biggest challenges in public health is the rising number of antibiotic resistant pathogens and the lack of novel antibiotics. In recent years there is a rising focus on fungi as sources of antimicrobial compounds due to their ability to produce a large variety of bioactive compounds and the observation that virtually every fungus may still contain yet unknown so called "cryptic," often silenced, compounds. These putative metabolites could include novel bioactive compounds. Considerable effort is spent on methods to induce production of these "cryptic" metabolites. One approach is the use of small molecule effectors, potentially influencing chromatin landscape in fungi. We observed that the supernatant of the fungus Doratomyces (D.) microsporus treated with valproic acid (VPA) displayed antimicrobial activity against Staphylococcus (S.) aureus and two methicillin resistant clinical S. aureus isolates. VPA treatment resulted in enhanced production of seven antimicrobial compounds: cyclo-(L-proline-L-methionine) (cPM), p-hydroxybenzaldehyde, cyclo-(phenylalanine-proline) (cFP), indole-3-carboxylic acid, phenylacetic acid (PAA) and indole-3-acetic acid. The production of the antimicrobial compound phenyllactic acid was exclusively detectable after VPA treatment. Furthermore three compounds, cPM, cFP, and PAA, were able to boost the antimicrobial activity of other antimicrobial compounds. cPM, for the first time isolated from fungi, and to a lesser extent PAA, are even able to decrease the minimal inhibitory concentration of ampicillin in MRSA strains. In conclusion we could show in this study that VPA treatment is a potent tool for induction of "cryptic" antimicrobial compound production in fungi, and that the induced compounds are not exclusively linked to the secondary metabolism. Furthermore this is the first discovery of the rare diketopiperazine cPM in fungi. Additionally we could demonstrate that cPM and PAA boost antibiotic activity against antibiotic resistant strains, suggesting a possible application in combinatorial antibiotic treatment against resistant pathogens.
authors.affiliation: Institute for Milk Hygiene, University of Veterinary Medicine ViennaVienna, Austria; Research Platform Bioactive Microbial Metabolites, Bioresources and Technologies Campus in TullnTulln an der Donau, Austria.
authors.forename: Christoph
authors.initials: C
authors.lastname: Zutz
authors.affiliation: Division of Chemistry of Renewables, Department of Chemistry, University of Natural Resources and Life Sciences, Vienna Tulln an der Donau, Austria.
authors.forename: Markus
authors.initials: M
authors.lastname: Bacher
authors.affiliation: Center for Analytical Chemistry, Department of Agrobiotechnology (IFA-Tulln), University of Natural Resources and Life Sciences, Vienna Tulln an der Donau, Austria.
authors.forename: Alexandra
authors.initials: A
authors.lastname: Parich
authors.affiliation: Research Platform Bioactive Microbial Metabolites, Bioresources and Technologies Campus in TullnTulln an der Donau, Austria; Center for Analytical Chemistry, Department of Agrobiotechnology (IFA-Tulln), University of Natural Resources and Life Sciences, ViennaTulln an der Donau, Austria.
authors.forename: Bernhard
authors.initials: B
authors.lastname: Kluger
authors.affiliation: Fungal Genetics and Genomics Unit, Department of Applied Genetics and Cell Biology, University of Natural Resources and Life Sciences, Vienna Tulln an der Donau, Austria.
authors.forename: Agnieszka
authors.initials: A
authors.lastname: Gacek-Matthews
authors.affiliation: Center for Analytical Chemistry, Department of Agrobiotechnology (IFA-Tulln), University of Natural Resources and Life Sciences, Vienna Tulln an der Donau, Austria.
authors.forename: Rainer
authors.initials: R
authors.lastname: Schuhmacher
authors.affiliation: Institute for Milk Hygiene, University of Veterinary Medicine Vienna Vienna, Austria.
authors.forename: Martin
authors.initials: M
authors.lastname: Wagner
authors.affiliation: Institute for Milk Hygiene, University of Veterinary Medicine Vienna Vienna, Austria.
authors.forename: Kathrin
authors.initials: K
authors.lastname: Rychli
authors.affiliation: Research Platform Bioactive Microbial Metabolites, Bioresources and Technologies Campus in TullnTulln an der Donau, Austria; Fungal Genetics and Genomics Unit, Department of Applied Genetics and Cell Biology, University of Natural Resources and Life Sciences, ViennaTulln an der Donau, Austria; Health and Environment Department, Bioresources, Austrian Institute of Technology GmbH, University and Research Campus TullnTulln an der Donau, Austria.
authors.forename: Joseph
authors.initials: J
authors.lastname: Strauss
keywords: Doratomyces; antimicrobial compounds; diketopiperazine; fungi; valproic acid