Elevated MIC Values of Imidazole Drugs against Aspergillus fumigatus Isolates with TR ₃₄ /L98H/S297T/F495I Mutation

Abstract

The use of azole fungicides in agriculture is believed to be one of the main reasons for the emergence of azole resistance in <i>Aspergillus fumigatus</i> Though widely used in agriculture, imidazole fungicides have not been linked to resistance in <i>A. fumigatus</i> This study showed that elevated MIC values of imidazole drugs were observed against <i>A. fumigatus</i> isolates with TR₃₄/L98H/S297T/F495I mutation, but not among isolates with TR₃₄/L98H mutation. Short-tandem-repeat (STR) typing analysis of 580 <i>A. fumigatus</i> isolates from 20 countries suggested that the majority of TR₃₄/L98H/S297T/F495I strains from China were genetically different from the predominant major clade comprising most of the azole-resistant strains and the strains with the same mutation from the Netherlands and Denmark. Alignments of sterol 14α-demethylase sequences suggested that F495I in <i>A. fumigatus</i> was orthologous to F506I in <i>Penicillium digitatum</i> and F489L in <i>Pyrenophora teres</i>, which have been reported to be associated with imidazole resistance. <i>In vitro</i> antifungal susceptibility testing of different recombinants with <i>cyp51A</i> mutations further confirmed the association of the 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 <i>A. fumigatus</i>.