Mechanisms involved in Aspergillus fumigatus antifungal drug adaptation

Aspergillus fumigatus is an opportunistic pathogenic mold responsible of invasive aspergillosis (IA) in immunocompromised patients. Antifungal therapies for the treatment of IA are limited to three drug classes. The azoles (e.g. voriconazole) represent the first-line treatment, while polyenes (amphotericin B) and echinocandins (e.g. caspofungin) are alternative therapies. Resistance to antifungal drugs is a concern. A. fumigatus exhibits some degree of natural tolerance to caspofungin with loss of efficacy of the drug at higher concentrations (a phenomenon known as the “paradoxical effect”). Moreover, acquired resistance to azoles consisting of mutations in the target gene (cyp51A) is emerging as a consequence of the widespread use of fungicides in agriculture. This work aims at deciphering the different mechanisms of the adaptive response of A. fumigatus leading to caspofungin tolerance and azole resistance. In the first part of the project, we investigated the network of the heat shock protein 90 (Hsp90) in caspofungin tolerance. Hsp90 is an essential molecular chaperone known to be essential for this process, but its pathway remains to be elucidated. We identified a yet unrevealed role of the mitochondrial respiratory chain (MRC) in caspofungin tolerance and paradoxical effect, which is dependent from Hsp90. In the second part of the project, we investigated the mechanisms of azole resistance of a laboratory generated A. fumigatus strain exhibiting pan-azole resistance in the absence of cyp51A mutations. Overexpression of efflux pumps genes (ABC and MFS transporters) were found to play a role in azole resistance of this strain. Transporter inhibitors such as milbemycin and Phe-Arg β-naphthylamide could potentiate the activity of azoles against A. fumigatus. This work provides further insights in these mechanisms of antifungal adaptation and resistance in A. fumigatus and could possibly identify novel therapeutic targets. -- Aspergillus fumigatus est une moisissure pathogène opportuniste responsable de ...