Retooling The Fungal Chemical Factory

Fungi suppress biosynthetic pathways for certain natural products when those compounds aren't needed. Natural products chemist Robert H. Cichewicz and colleagues at the University of Oklahoma, Norman, have now figured out a way to induce fungi to reactivate some of those silenced pathways (Org. Biomol. Chem., DOI: 10.1039/b804701d). The method could "greatly expand the suite of biologically active small molecules obtained from fungi and increase the odds of discovering new drugs," notes Jon Clardy, who studies biologically active natural products at Harvard Medical School. To block production of a given natural product, fungal enzymes prevent transcription of the relevant genes by tagging DNA with methyl groups or removing acetyl groups from the protein spools that DNA is wound around. Cichewicz' team reversed this process with 5-azacytidine and suberoylanilide hydroxamic acid. Those small molecules interfere with the activity of the enzymes that alter gene expression. As a result the fungi churned out an altered assortment of natural products, including the novel compounds shown, where R is p-hydroxybenzoate or p-hydroxybenzylcarbonate. Cichewicz says the new approach "enhances the speed and reduces the cost of discovering new natural products from microorganisms."