<i>Aspergillus fumigatus </i>secondary metabolite pyripyropene is important for the dual biofilm formation with <i>Pseudomonas aeruginosa</i>

The human pathogenic fungus <i>Aspergillus fumigatus</i> establishes dual biofilm interactions in the lungs with the pathogenic bacterium <i>Pseudomonas aeruginosa</i>. Screening of 21 <i>A. fumigatus </i>null mutants revealed 7 mutants (two GPCRs, three MAPK receptors, a G-alpha protein, and one histidine kinase receptor) with reduced biofilm formation, specifically in the presence of <i>P. aeruginosa</i>. Transcriptional profiling and metabolomics analysis of secondary metabolites produced by one of these mutants, Δ<i>gpaB</i> (<i>gpaB</i> encodes a G-alpha protein), showed GpaB controls the production of several important metabolites for the dual biofilm interaction, including pyripyropene A, a potent inhibitor of mammalian acyl-CoA cholesterol acyltransferase. Deletion of <i>pyr2</i>, encoding a non-reducing polyketide synthase, essential for pyripyropene biosynthesis, showed reduced <i>A. fumigatus </i>Δ<i>pyr2-P. aeruginosa</i> biofilm<i> </i>growth, altered macrophage responses, and attenuated mouse virulence in a chemotherapeutic murine model. We identified pyripyropene as a novel player in the ecology and pathogenic interactions of this important human fungal pathogen.