Host–Pathogen Interaction Activated Biosynthesis of Natural Products

The way immune cells attack pathogenic microorganisms might trigger pathogens to produce compounds that promote their survival. Based on this idea, we constructed a coculture system of pathogenic fungi and immune cells and isolated fumigatinolactone (<b>1</b>) as a new natural product by coculture of <i>Aspergillus fumigatus</i> IFM 60237 with RAW264 mouse macrophage-like cells. Fumigatinolactone (<b>1</b>) was produced via a nonenzymatic coupling reaction between fumigatin (<b>4</b>) and a new type of intermediate fumarylazlactone (<b>5</b>). An investigation of the interaction mechanism between the fungi and cells revealed that the survival interaction between pathogen and immune cells played key roles. Surprisingly, fungi showed a response to nitric oxide (NO), which was produced by macrophages, resulting in the production of <b>4</b>. In addition, an iron starvation condition triggered the production of <b>5</b>. Finally, <b>1</b> was obtained by these two mechanisms. Furthermore, compounds <b>1</b>-<b>4</b>, particularly <b>4</b>, showed inhibition of NO production from RAW264, which might be a defense action for macrophage by fungi. This is the first example of elucidation of interaction mechanisms between pathogen and immune cells for activation of silent genes to produce a new compound. These findings suggest that host-pathogen survival interaction may increase the production of secondary metabolites from fungi.