Abstract
BackgroundThe inherent potential of filamentous fungi, especially of Ascomycota, for producing diverse bioactive metabolites remains largely silent under standard laboratory culture conditions. Innumerable strategies have been described to trigger their production, one of the simplest being manipulation of the growth media composition. Supplementing media with ionic liquids surprisingly enhanced the diversity of extracellular metabolites generated by penicillia. This finding led us to evaluate the impact of ionic liquids’ stimuli on the fungal metabolism in Aspergillus nidulans and how it reflects on the biosynthesis of secondary metabolites (SMs).ResultsWhole transcriptional profiling showed that exposure to 0.7 M cholinium chloride or 1-ethyl-3-methylimidazolium chloride dramatically affected expression of genes encoding both primary and secondary metabolism. Both ionic liquids apparently induced stress responses and detoxification mechanisms but response profiles to each stimulus were unique. Primary metabolism was up-regulated by choline, but down-regulated by 1-ethyl-3-methylimidazolium chloride; both stimulated production of acetyl-CoA (key precursor to numerous SMs) and non proteinogenic amino acids (building blocks of bioactive classes of SMs). In total, twenty one of the sixty six described backbone genes underwent up-regulation. Accordingly, differential analysis of the fungal metabolome showed that supplementing growth media with ionic liquids resulted in ca. 40 differentially accumulated ion masses compared to control conditions. In particular, it stimulated production of monodictyphenone and orsellinic acid, otherwise cryptic. Expression levels of genes encoding corresponding polyketide biosynthetic enzymes (i.e. backbone genes) increased compared to control conditions. The corresponding metabolite extracts showed increased cell polarity modulation potential in an ex vivo whole tissue assay (Thelial Live Targeted Epithelia; theLiTE™).ConclusionsIonic liquids, a diverse class of chemicals composed solely of ions, can provide an unexpected means to further resolve the diversity of natural compounds, guiding discovery of fungal metabolites with clinical potential.Electronic supplementary materialThe online version of this article (doi:10.1186/s12864-016-2577-6) contains supplementary material, which is available to authorized users.
Highlights
The inherent potential of filamentous fungi, especially of Ascomycota, for producing diverse bioactive metabolites remains largely silent under standard laboratory culture conditions
Aspergillus nidulans differential metabolic footprints under ionic liquid stimuli The diversity of compounds in the metabolic footprint of fungi depends on growth media composition [42]
Transcriptional profiling was used for the first time to evaluate ionic liquids broad impacts on both primary and secondary metabolism of A. nidulans
Summary
The inherent potential of filamentous fungi, especially of Ascomycota, for producing diverse bioactive metabolites remains largely silent under standard laboratory culture conditions. Supplementing media with ionic liquids surprisingly enhanced the diversity of extracellular metabolites generated by penicillia This finding led us to evaluate the impact of ionic liquids’ stimuli on the fungal metabolism in Aspergillus nidulans and how it reflects on the biosynthesis of secondary metabolites (SMs). Several strategies have been described to stimulate production of particular SMs; some require prior knowledge of genomic sequences, relying on manipulation of targeted genes encoding components of either secondary metabolism [22] (e.g. aspoquinolones A– D [23]) or regulatory pathways (e.g. monodictyphenone [24] and asperthecin [9]). Selected chemical stimuli are representative of the most studied families of ionic liquids and represent opposite ends of the spectrum regarding toxicity and recalcitrance Both compounds increase numerous mycelial stress-responsive proteins (e.g. drug transporter proteins) and induce particular developmental changes and production of certain osmolytes [31]. This study sheds first light on the vast potential of ionic liquids to reveal the diversity of natural compound biosynthesis potential in fungi
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