Large-Scale Metabolomics Reveals a Complex Response of Aspergillus nidulans to Epigenetic Perturbation

Jessica C. Albright, Matthew T. Henke, Alexandra A. Soukup, Ryan A. McClure, Regan James Thomson, Nancy P. Keller, Neil L Kelleher*

*Corresponding author for this work

Research output: Contribution to journalArticle

40 Scopus citations

Abstract

The microbial world offers a rich source of bioactive compounds for those able to sift through it. Technologies capable of quantitatively detecting natural products while simultaneously identifying known compounds would expedite the search for new pharmaceutical leads. Prior efforts have targeted histone deacetylases in fungi to globally activate the production of new secondary metabolites, yet no study has directly assessed its effects with minimal bias at the metabolomic level. Using untargeted metabolomics, we monitored changes in >1000 small molecules secreted from the model fungus, Aspergillus nidulans, following genetic or chemical reductions in histone deacetylase activity (HDACi). Through quantitative, differential analyses, we found that nearly equal numbers of compounds were up- and down-regulated by >100 fold. We detected products from both known and unknown biosynthetic pathways and discovered that A. nidulans is capable of producing fellutamides, proteasome inhibitors whose expression was induced by ∼100 fold or greater upon HDACi. This work adds momentum to an "omics"-driven resurgence in natural products research, where direct detection replaces bioactivity as the primary screen for new pharmacophores.

Original languageEnglish (US)
Pages (from-to)1535-1541
Number of pages7
JournalACS chemical biology
Volume10
Issue number6
DOIs
StatePublished - Jun 19 2015

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Medicine

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