Heterologous expression of a natural product biosynthetic gene cluster from Cordyceps militaris

Cordyceps is a genus of ascomycete fungi widely used in old Chinese medicine, and many investigations have focus on uncovering their biological activities. Until now, only a few compounds have been identified from Cordyceps, mainly due to their poor yield. So as to make full use of Cordyceps, we used the strategy of genome mining and heterologous expression to discover natural products (NPs) from Cordyceps militaris. Analysis of the genome sequence of Cordyceps militaris CM01 showed the presence of a cryptic gene cluster encoding a highly-reducing polyketide synthetase (HR-PKS), enoyl-reductase (ER) and cytochrome P450. Heterologous expression in Aspergillus nidulans enabled the identification of two new polyketides, cordypyrone A and B. Their structures were determined by 1D and 2D NMR techniques. They showed only modest activities against pathogenic bacteria including methicillin-resistant Staphylococcus aureus (MRSA), Mycobacteria tuberculosis and Bacillus cereus.