Distinct transcriptional responses to fludioxonil in Aspergillus fumigatus and its ΔtcsC and Δskn7 mutants reveal a crucial role for Skn7 in the cell wall reorganizations triggered by this antifungal

Sebastian Schruefer (1) , Annica Pschibul (2) , Sarah Sze Wah Wong (3) , Tongta Sae-Ong (2) , Thomas Wolf (2) , Sascha Schäuble (2) , Gianni Panagiotou (2) , Axel Brakhage (2) , Vishukumar Aimanianda (3) , Olaf Kniemeyer (2) , Frank Ebel (1)

1 LMU - Ludwig Maximilian University [Munich] = Ludwig Maximilians Universität München
2 Leibniz Institute for Natural Product Research and Infection Biology (Hans Knoell Institute)
3 Mycologie moléculaire - Molecular Mycology

Background Aspergillus fumigatus is a major fungal pathogen that causes severe problems due to its increasing resistance to many therapeutic agents. Fludioxonil is a compound that triggers a lethal activation of the fungal-specific High Osmolarity Glycerol pathway. Its pronounced antifungal activity against A. fumigatus and other pathogenic molds renders this agent an attractive lead substance for the development of new therapeutics. The group III hydride histidine kinase TcsC and its downstream target Skn7 are key elements of the multistep phosphorelay that represents the initial section of the High Osmolarity Glycerol pathway. Loss of tcs C results in resistance to fludioxonil, whereas a Δ skn 7 mutant is partially, but not completely resistant. Results In this study, we compared the fludioxonil-induced transcriptional responses in the Δ tcs C and Δ skn 7 mutant and their parental A. fumigatus strain. The number of differentially expressed genes correlates well with the susceptibility level of the individual strains. The wild type and, to a lesser extend also the Δ skn 7 mutant, showed a multi-faceted stress response involving genes linked to ribosomal and peroxisomal function, iron homeostasis and oxidative stress. A marked difference between the sensitive wild type and the largely resistant Δ skn 7 mutant was evident for many cell wall-related genes and in particular those involved in the biosynthesis of chitin. Biochemical data corroborate this differential gene expression that does not occur in response to hyperosmotic stress. Conclusions Our data reveal that fludioxonil induces a strong and TcsC-dependent stress that affects many aspects of the cellular machinery. The data also demonstrate a link between Skn7 and the cell wall reorganizations that foster the characteristic ballooning and the subsequent lysis of fludioxonil-treated cells.

Mots clés: Aspergillus fumigatus; Fludioxonil; HOG pathway; Skn7; TcsC; Multistep phosphorelay

Domaines: Mycologie; Génomique, Transcriptomique et Protéomique [q-bio.GN]; Pharmacologie

Sebastian Schruefer, Annica Pschibul, Sarah Sze Wah Wong, Tongta Sae-Ong, Thomas Wolf, et al.. Distinct transcriptional responses to fludioxonil in Aspergillus fumigatus and its ΔtcsC and Δskn7 mutants reveal a crucial role for Skn7 in the cell wall reorganizations triggered by this antifungal. BMC Genomics, 2023, 24 (1), pp.684. ⟨10.1186/s12864-023-09777-5⟩. ⟨hal-04335237⟩