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 the newest class of approved antifungal drugs to treat aspergillosis. Although caspofungin is very effective against other human fungal pathogens, it is fungistatic against A. fumigatus and recommended as second-line therapy of invasive aspergillosis. Resistance to caspofungin in A. fumigatus have been linked to mutations in the FKS1 gene that encodes the target enzyme of the drug, beta-1,3-glucan synthase. However, tolerance to high caspofungin concentrations, a phenomenon called caspofungin paradoxical effect (CPE), is also important for subsequent adaptation and drug resistance evolution. Here, we have identified and characterized several 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 at least 11 TFs that had reduced CPE and nine of them showed to be more sensitive to lower caspofungin concentrations.
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