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posted on 2020-05-15, 18:53 authored by Gustavo GoldmanGustavo Goldman

Aspergillus fumigatus is the leading cause of pulmonary fungal diseases. Azoles have been used for many years as the main antifungal agents to treat and prevent invasive aspergillosis. However, in the last ten years there are several reports of azole resistance in A. fumigatus and new strategies are needed to combat invasive aspergillosis. Caspofungin is effective against other human fungal pathogens, but it is only fungistatic against A. fumigatus. Resistance to caspofungin in A. fumigatus have been linked to mutations in the fksA gene that encodes the target enzyme of the drug, β-1,3-glucan synthase. However, tolerance to high caspofungin concentrations, a phenomenon known as caspofungin paradoxical effect (CPE), is also important for subsequent adaptation and drug resistance evolution. Here, we have identified and characterized the transcription factors involved in the response to CPE by screening an A. fumigatus library of 484 null transcription factors (TFs) in CPE drug concentrations. We have identified eleven TFs that had reduced CPE encoding proteins involved in the basal modulation of the RNA polymerase II initiation sites, calcium metabolism and cell wall remodelling. One of theseTFs FhdA was important for mitochondrial respiratory function and iron metabolism. The ΔfhdA mutant had decreased growth when exposed to Congo Red or at high temperature. RNAseq analysis and further experimental validation indicate that the ΔfhdA mutant showed diminished respiratory capacity, probably affecting several pathways related to the caspofungin tolerance and resistance. Our results provide the foundation to understand signaling pathways that are important for caspofungin tolerance and resistance.

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FAPESP, Brazil

CNPq, Brazil

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