Abstract
The recent increase in azole-resistant Aspergillus fumigatus is a global concern. Identifying the mutations that confer azole resistance is essential for developing novel methods for prompt diagnosis and effective drug treatment. We screened A. fumigatus clinical isolates for novel mutations conferring azole resistance. We compared the genomic sequences of susceptible and resistant isolates without mutations in cyp51A (non-cyp51A) and found mutations in hmg1 and erg6 involved in ergosterol biosynthesis. We also found the novel mutations in these genes in azole-resistant isolates with different genetic backgrounds. The resistant isolates with mutations in hmg1 showed increased intracellular ergosterol levels compared with susceptible isolates. This finding supports the concept that the ergosterol level is a determinant for resistance to any class of azoles. Multiple isolates with increased resistance to azole possessed a mutation in hmg1, indicating that this mutation is widely present in non-cyp51A azole-resistant A. fumigatus.
Highlights
The recent increase in azole-resistant Aspergillus fumigatus is a global concern
We recovered a total of 19 A. fumigatus isolates from 1 patient on 9 testing dates during September 2011–May 2016 (Tables 1, 2)
We found no differences between the first and third isolates regarding sensitivity to terbinafine, which interferes with the early stage of ergosterol biosynthesis, and fenpropimorph, which inhibits ergosterol biosynthesis
Summary
The recent increase in azole-resistant Aspergillus fumigatus is a global concern. Identifying the mutations that confer azole resistance is essential for developing novel methods for prompt diagnosis and effective drug treatment. To detect mutations in cyp51A, erg6, and hmg1 genes, we performed PCR amplification and sequenced these regions using appropriately designed primers *AMPH, amphotericin B; IFM, Institute of Food Microbiology ( Medical Mycology Research Center), Chiba University, Chiba City, Japan; ITCZ, itraconazole; MCFG, micafungin; MEC, minimal effective concentration; ND, not determined; PSCZ, posaconazole; VRCZ, voriconazole; –, no mutation.
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