Elevated MIC values to imidazole drugs among Aspergillus fumigatus isolates with TR34/L98H/S297T/F495I mutation [PublishAheadOfPrint]

Use of azole fungicides in agriculture is believed to be one of the main reasons for the emergence of azole resistance in Aspergillus fumigatus. Although widely used in agriculture, imidazole fungicides have not been linked to resistance in A. fumigatus. This study showed that elevated MIC values to imidazole drugs were observed among A. fumigatus isolates with TR₃₄/L98H/S297T/F495I mutation, but not among isolates with TR₃₄/L98H mutation. The STR typing analysis of 580 A. fumigatus isolates from 20 countries suggested that the majority of TR₃₄/L98H/S297T/F495I strains from China were genetically different from the predominated major clade consisted of most of the azole resistant strains and the strains with the same mutation from the Netherlands and Denmark. Alignments of sterol 14α-demethylase sequences implicated that F495I in A. fumigatus was orthologous to F506I in Penicillium digitatum and F489L in Pyrenophora teres, which have been reported to be associated with imidazole resistance. The in vitro antifungal susceptibility testing of different recombinants of cyp51A mutations further confirms the association of F495I mutation with imidazole resistance. In conclusion, this study suggested that environmental use of imidazole fungicides might confer selection pressure for the emergence of azole resistance in A. fumigatus.

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