Whole-chromosome duplications drive antimicrobial resistance in Aspergillus fumigatus

Aneuploidy causes genome plasticity and enables adaptive responses that confer drug resistance in eukaryotes ranging from fungal pathogens to human cancer cells. Aspergillus fumigatus is a soil-resident fungus and the most common cause of invasive fungal infections globally. Aspergillosis has an alarmingly high mortality rate due in part to treatment failure resulting from widespread antimicrobial resistance and an ability of the fungus to dynamically adapt to changing environmental and host conditions. Our understanding of these treatment failures is hindered by gaps in knowledge about how this organism adapts to resist antimicrobial stress. We find that exposure to FK506, an antifungal and immunosuppressive compound produced by Streptomyces, selects for whole-chromosome aneuploidy in this fungus. Growth without FK506 results in rapid aneuploid chromosome loss and reversion to the euploid, drug-susceptible state. These chromosome duplications also reduce susceptibility to clinically-used azole antifungals, underscoring the utility of aneuploidy as a dynamic stress adaptation strategy. Transcriptomic analysis revealed that Chr7 disomy leads to induction of the normally-silent neosartoricin biosynthetic gene cluster in response to FK506 exposure, and we demonstrate that constitutive genetic induction of this cluster recapitulates in the euploid background the response to FK506 in the aneuploid state. We further show that this response is independent from the production of neosartoricin, suggesting a role for cross-pathway metabolic changes resulting from activation of this gene cluster or from the aneuploid state. This study represents a major advance in understanding how aneuploidy leads to transient adaptation and antimicrobial drug resistance in a global human fungal pathogen. Highlights - fumigatus rapidly gains and loses chromosomes in response to antimicrobial stress. - Aneuploidy leads to large-scale transcriptional and metabolic changes. - Overexpression of nscR is sufficient to confer FK506 tolerance in the euploid. - Aneuploidy reduces susceptibility to both FK506 and azole antifungals.