Aspergillus fumigatus secondary metabolite pyripyropene is important for the dual biofilm formation with Pseudomonas aeruginosa

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de Castro, Patricia Alves ; Akiyama, Daniel Yuri ; Pinzan, Camila Figueiredo ; dos Reis, Thaila Fernanda ; Delbaje, Endrews ; Rocha, Peter ; Izidoro, Mario Augusto ; Schenkman, Sergio ; Sugimoto, Shinya ; Takeshita, Norio ; Steffen, Karin ; Aycock, Jessica L. ; Dolan, Stephen K. ; Rokas, Antonis ; Fill, Taicia ; Goldman, Gustavo H.

• Document type: Journal article
• Source: MBIO; v. 16, n. 4, p. 31-pg., 2025-03-17.

Abstract

The human pathogenic fungus Aspergillus fumigatus establishes dual biofilm interactions in the lungs with the pathogenic bacterium Pseudomonas aeruginosa. Screening of 21 A. fumigatus null mutants revealed seven mutants (two G protein-coupled receptors, three mitogen-activated protein kinase receptors, a G alpha protein, and one histidine kinase receptor) with reduced biofilm formation, specifically in the presence of P. aeruginosa. Transcriptional profiling and metabolomics analysis of secondary metabolites produced by one of these mutants, Delta gpaB (gpaB 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 pyr2, encoding a non-reducing polyketide synthase essential for pyripyropene biosynthesis, showed reduced A. fumigatus Delta pyr2-P. aeruginosa biofilm 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. (AU)

• FAPESP's process: 21/12515-1 - Oxidative stress response mechanisms in phosphorylation of eIF2± and AMPK in T. cruzi
• Grantee: Mirella Aricó Vieitas Costa
• Support Opportunities: Scholarships in Brazil - Doctorate (Direct)
• FAPESP's process: 21/04977-5 - The identification of new pathways and compounds that can enhance caspofungin activity against Aspergillus fumigatus
• Grantee: Gustavo Henrique Goldman
• Support Opportunities: Research Projects - Thematic Grants
• FAPESP's process: 21/07038-0 - Chemical and molecular investigation of natural products involved in Penicillium brasilianum-hosts interactions
• Grantee: Daniel Yuri Akiyama
• Support Opportunities: Scholarships in Brazil - Doctorate (Direct)
• FAPESP's process: 24/11166-1 - A G-alpha protein mediates the interaction between Aspergillus fumigatus and Pseudomonas aeruginosa during biofilm formation
• Grantee: Gustavo Henrique Goldman
• Support Opportunities: Regular Research Grants