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Azole compounds are the primary therapy for patients with diseases caused by  Aspergillus fumigatus . However, prolonged treatment may cause resistance to develop, which is associated with treatment failure. The azole target  cyp51A  is a hotspot for mutations that confer phenotypic resistance, but in an increasing number of resistant isolates the underlying mechanism remains unknown. Here, we report the discovery of a novel resistance mechanism, caused by a mutation in the  CCAAT -binding transcription factor complex subunit HapE. From one patient, four  A. fumigatus  isolates were serially collected. The last two isolates developed an azole resistant phenotype during prolonged azole therapy. Because the resistant isolates contained a wild type  cyp51A  gene and the isolates were isogenic, the complete genomes of the last susceptible isolate and the first resistant isolate (taken 17 weeks apart) were sequenced using Illumina technology to identify the resistance conferring mutation. By comparing the genome sequences to each other as well as to two  A. fumigatus  reference genomes, several potential non-synonymous mutations in protein-coding regions were identified, six of which could be confirmed by PCR and Sanger sequencing. Subsequent sexual crossing experiments showed that resistant progeny always contained a P88L substitution in HapE, while the presence of the other five mutations did not correlate with resistance in the progeny. Cloning the mutated  hapE  gene into the azole susceptible  akuB   KU80  strain showed that the HapE P88L mutation by itself could confer the resistant phenotype. This is the first time that whole genome sequencing and sexual crossing strategies have been used to find the genetic basis of a trait of interest in  A. fumigatus . The discovery may help understand alternate pathways for azole resistance in  A. fumigatus  with implications for the molecular diagnosis of resistance and drug discovery.

Discovery of a hapE Mutation That Causes Azole Resistance in Aspergillus fumigatus through Whole Genome Sequencing and Sexual Crossing