The Influence of Aspergillus fumigatus Fatty Acid Oxygenases PpoA and PpoC on Caspofungin Susceptibility

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Delbaje, Endrews ; de Castro, Patricia Alves ; Calise, Dante G. ; Mengyao, Niu ; Horta, Maria Augusta Crivelente ; Akiyama, Daniel Yuri ; Pontes, Joao Guilherme ; Fill, Taicia ; Kniemeyer, Olaf ; Kruger, Thomas ; Brakhage, Axel A. ; Wong, Koon Ho ; Keller, Nancy P. ; Goldman, Gustavo H.

• Document type: Journal article
• Source: JOURNAL OF FUNGI; v. 10, n. 11, p. 23-pg., 2024-11-01.

Abstract

Aspergillus fumigatus can cause invasive pulmonary aspergillosis (IPA). Fungicidal azoles and fungistatic caspofungin (CAS) are the first- and second-line therapies, respectively, used to treat IPA. Treatment of A. fumigatus with CAS or micafungin induces the production of the oxylipin 5,8-diHODE by the fungal oxygenase PpoA. For this article, we investigated the influence of ppo genes, which encode the fatty acid oxygenases responsible for oxylipin biosynthesis, on CAS tolerance. The influence of PpoA and PpoC on CAS tolerance is mediated by MpkA phosphorylation and protein kinase A (PKA) activity. RNAseq transcriptional profiling and the label-free quantitative proteomics of the ppoA and ppoC mutants showed that differentially expressed genes and proteins are related to secondary metabolites and carbohydrate metabolism. We also characterized two clinical isolates, CM7555 and IFM61407, which decrease and increase susceptibility to CAS, respectively. CM7555 does not exhibit increased oxylipin production in the presence of CAS but oxylipin induction upon CAS exposure is increased in IFM61407, suggesting that oxylipins are not the only mechanism involved in CAS tolerance in these isolates. Upon CAS exposure, CM7555 has higher MpkA phosphorylation and PKA activity than IFM61407. Our results reveal the different aspects and genetic determinants involved in A. fumigatus CAS tolerance. (AU)

• FAPESP's process: 23/00206-0 - Characterization of mitogenomes of Aspergillus fumigatus populations with strains resistant and susceptible to antifungal drugs
• Grantee: Endrews Delbaje
• Support Opportunities: Scholarships in Brazil - Post-Doctoral
• FAPESP's process: 22/02992-0 - Deciphering the role of secondary metabolites in the chemical interaction between phytopathogens and the citrus host
• Grantee: Taicia Pacheco Fill
• Support Opportunities: Research Grants - Initial Project
• 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