FN2-6 | Novel insights in the antifungal activity of fludioxonil in Aspergillus fumigatus.

摘要

Group III hybrid histidine kinases are fungal-specific proteins and assumed to function as sensor kinases of the High Osmolarity Glycerol (HOG) pathway, a major fungal stress pathway. Apart from their role in stress response, group III hybrid histidine kinases are also attractive targets for antifungals. Pyrrolnitrin, which is produced by certain Gram-negative bacteria, and its chemical derivative fludioxonil are strong activators of the HOG pathway. This artifical activation triggers a massive swelling and leads finally to lysis of the fungal cells. The antifungal activity of fludioxonil or pyrrolnitrin depends on the presence of a group III hybrid histidine kinase. In the opportunistic mold Aspergillus fumigatus, the respective enzyme was designated TcsC. TcsC phos-phorylates the downstream phosphotransfer protein Ypd1 that in turn activates the two response regulators Ssk1 and Skn7. Skn7 is a transcription factor, while Ssk1 is the first enzyme of a MAP kinase module that terminates in SakA. Using A. fumigatus deletion mutants in ssk1, sakA, skn7 and tcsC, we have investigated the localization of these proteins and their functional role in the antifungal activity of fludioxonil. Unexpectedly, our data indicate that Skn7 is much more important in this context than the main branch of the HOG pathway, represented by Ssk1 and SakA. To further unravel the function of Skn7, we have also analysed the fludioxonil-triggered transcriptional response in the Askn7 mutant, the AtcsC mutant and the corresponding wild type strain. Based on these data, we propose a novel model for the antifungal activity of fludioxonil and related agents in A. fumigatus.