A 23 bp Promoter Deletion Associated With Voriconazole Resistance in Clinical and Environmental Isolates of .

In the fungal pathogen , resistance to azole antifungals is often linked to mutations in , a gene that encodes the azole antifungal drug target lanosterol 14α-demethylase. The aim of this study was to investigate whether similar changes could be associated with azole resistance in a Malaysian species complex (FSSC) isolate collection. Most (11 of 15) clinical FSSC isolates were and the majority (6 of 10) of environmental isolates were strains. All 25 FSSC isolates had high minimum inhibitory concentrations (MICs) for itraconazole and posaconazole, low MICs for amphotericin B, and various (1 to >32 mg/l) voriconazole susceptibilities. There was a tight association between a 23 bp promoter deletion and high (>32 mg/l) voriconazole MICs; of 19 FSSC strains sequenced, nine isolates had voriconazole MICs > 32 mg/l, and they all contained the 23 bp promoter deletion, although it was absent in the ten remaining isolates with low (≤12 mg/l) voriconazole MICs. Surprisingly, this association between voriconazole resistance and the 23 bp promoter deletion held true across species boundaries. It was randomly distributed within and across species boundaries and both types of FSSC isolates were found among environmental and clinical isolates. Three randomly selected isolates with low (≤8 mg/l) voriconazole MICs had significantly lower (1.3-7.5 times) mRNA expression levels than three randomly selected isolates with high (>32 mg/l) voriconazole MICs. expression levels, however, were equally strongly induced (~6,500-fold) by voriconazole in two representative strains reaching levels, after 80 min of induction, that were comparable to those of . Our results suggest that FSSC isolates with high voriconazole MICs have a 23 bp promoter deletion that provides a potentially useful marker for voriconazole resistance in FSSC isolates. Early detection of possible voriconazole resistance is critical for choosing the correct treatment option for patients with invasive fusariosis.