A ground-breaking method of getting fungi to produce normally 'hidden' compounds has been demonstrated by US scientists, opening the door on a whole new range of natural products. 

Fungi produce a wide variety of natural products, including toxins (such as the amanitins, primarily responsible for the toxicity of the death cap fungus) and life-saving drugs (e.g. penicillin). With such great potential for producing important substances, the genetics of fungi have come under much scrutiny, especially since gene sequencing became a relatively routine operation. Now, Robert Cichewicz and colleagues at the University of Oklahoma have shown how metabolic pathways that are normally 'silent' can be activated, providing access to new natural products, and thus insights into fungal biochemistry. 

When the genes coding for natural products from fungi were first sequenced, says Cichewicz, much to everyone's surprise, many fungi were found to harbour a wealth of genes encoding for the production of many times the number of observed natural products. The conclusion was that when fungi do not need these natural products, they inhibit the transcription of the DNA that codes for the proteins that make them, thus preventing their biosynthesis. Knowing what these mystery compounds are, says Cichewicz, would be very important for the development of new medicines, as well as for understanding the ecological roles that fungi play. 

It was already known that this DNA is inactive because it is scrunched up in a globular form called heterochromatin. In order to access the 'silent' natural product pathways, says Cichewicz, they looked for ways by which they could enable the inactivated DNA to go about its work. They hypothesised that treating fungal cultures with small molecules known to interfere with the formation of the heterochromatin would allow the DNA to 'unwind' and become active, thus turning on these 'silent' natural product pathways. 

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, resulted in the 'dramatic restructuring' of its natural product output, with two completely new natural products being isolated. Identifying novel compounds like this, he says, is 'essential' for finding potential new drugs. 

The new approach impresses Jon Clardy at the Harvard Medical School, Boston, USA, who says that it could 'greatly expand the suite of biologically active small molecules obtained from fungi' and that it 'capitalizes 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, because, says Cichewicz, natural products are the means by which they 'communicate' with organisms around them. In essence, he says, 'we are now discovering chemical means for listening to what fungi are saying.'

David J Barden