"Silent" fungus metabolism awakened for new natural products

Fungi produce a wide variety of natural products, including potent toxins – for example, the amanitins, primarily responsible for the toxicity of the death cap fungus – and life-saving drugs such as penicillin. As a result, the genetics of fungi have generated much interest in recent years.

Now, Robert Cichewicz and colleagues at the University of Oklahoma, Norman, US, have shown that metabolic pathways that are normally ‘silent’ can be re-activated to make new compounds, in work published in the Royal Society of Chemistry journal Organic & Biomolecular Chemistry.

Many fungi have a wealth of genes encoding for far more natural products than they actually produce, says Cichewicz. The explanation is thought to be that when fungi do not need certain compounds, they inhibit the transcription of the DNA that codes for the proteins that make them, preventing their biosynthesis.

Knowing what these mystery compounds are could be very important for the development of new medicines, as well as for helping us to understand the ecological roles that fungi play, claims Cichewicz.

The DNA involved is inhibited by being scrunched up in a globular form called heterochromatin. To activate this DNA and turn on these ‘silent’ natural product pathways, the team decided to treat fungal cultures with small molecules that interfere with the formation of the heterochromatin – allowing the DNA to be transcripted.

To show their idea in action, the researchers took a culture of Cladosporium cladosporioides, a tidal pool fungus, and treated it separately with 5-azacytidine and suberoylanilide hydroxamic acid. Both treatments, says Cichewicz, dramatically changed the natural product output of the fungus, with two completely new natural products being isolated.

The new approach impresses Jon Clardy at the Harvard Medical School, Boston, US, who says that it could ‘greatly expand the suite of biologically active small molecules obtained from fungi’ and that it ‘capitalises on recent developments in drug discovery to increase the odds of discovering new drugs’.

The results also have important implications for research into fungi and other microorganisms, explains Cichewicz. Natural products are the means by which fungi ‘communicate’ with organisms around them, so we are in essence, he says, ‘discovering chemical means for listening to what fungi are saying’.