Large-Scale Metabolomics Reveals a Complex Response
of <i>Aspergillus nidulans</i> to Epigenetic Perturbation
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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, <i>Aspergillus
nidulans</i>, 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 <i>A. nidulans</i> 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