New Insights into the Cyp51 Contribution to Azole Resistance in Section .

Invasive aspergillosis (IA) is a severe condition mainly caused by , although other species of the genus, such as section members, can also be involved. Voriconazole (VRC) is the recommended treatment for IA; however, the prevalence of azole-resistant isolates has alarmingly increased in recent years, and the underlying resistance mechanisms in non- species remain unclear. We have determined the susceptibility of 36 strains from section to VRC, posaconazole (POS), and itraconazole (ITC), and we have explored the role of Cyp51A and Cyp51B, both targets of azoles, in azole resistance. The three drugs were highly active; POS displayed the best activity, while ITC and VRC showed MICs above the established epidemiological cutoff values in 9 and 16% of the strains, respectively. Furthermore, expression studies of and in control condition and after VRC exposure were performed in 14 strains with different VRC susceptibility. We found higher transcription of , which was upregulated upon VRC exposure, but no correlation between MICs and transcription levels was observed. In addition, sequence analyses revealed nonsynonymous mutations present in both, wild-type and non-wild-type strains of and Nevertheless, a few mutations were exclusively present in non-wild-type strains. Altogether, our results suggest that azole resistance in section is not clearly explained by Cyp51A protein alteration or by gene upregulation, which indicates that other mechanisms might be involved.