In-host developed azole-resistant Aspergillus Flavus

Aspergillus flavus is a pathogenic fungal species that can cause pulmonary aspergillosis and triazole compounds are used for the treatment of these infections. Prolonged exposure to azoles may induce compensatory mutations in the A. flavus genome resulting in azole resistance. Here we characterize a series of 11 isogenic A. flavus strains isolated from a patient with pulmonary aspergillosis. Over a period of three months, the initially azole susceptible strain developed itraconazole and voriconazole resistance. Short tandem repeat analysis and whole genome sequencing revealed a high genetic relatedness of all isolates indicating an infection with one single isolate. In contrast, the isolates were macroscopically highly diverse, suggesting an adaptation to the environment due to (epi)genetic changes. Whole genome sequencing of susceptible and azole resistant strains showed a number of mutations that might be associated with azole resistance. The majority of resistant strains contain a Y119F mutation in the Cyp51A gene which corresponds to the Y121F mutation found in A. fumigatus. One azole resistant strain demonstrated a divergent set of mutations, including a V99A mutation in a major facilitator superfamily (MSF) multidrug transporter.