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 Though widely used in agriculture, imidazole fungicides have not been linked to resistance in This study showed that elevated MIC values of imidazole drugs were observed against isolates with TR/L98H/S297T/F495I mutation, but not among isolates with TR/L98H mutation. Short-tandem-repeat (STR) typing analysis of 580 isolates from 20 countries suggested that the majority of TR/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 was orthologous to F506I in and F489L in , which have been reported to be associated with imidazole resistance. antifungal susceptibility testing of different recombinants with 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.

Aspergillus fumigatus Clinical Isolates Carrying CYP51A with TR34/L98H/S297T/F495I Substitutions Detected after Four-Year Retrospective Azole Resistance Screening in Brazil

“…Short tandem repeat (STR) typing analysis for nine microsatellite markers, 2A, 2B, 2C, 3A, 3B, 3C, 4A, 4B, and 4C (16), showed high levels of similarity between the two isolates and clinical isolates with the same mutations reported from the Netherlands, Denmark, and China, as well as environmental isolates from Taiwan (Fig. 2) (16,17).…”

Genome-Wide Comparative Analysis of Aspergillus fumigatus Strains: The Reference Genome as a Matter of Concern

“…Regarding azole resistance mechanisms, Cyp51A protein is the target of these drugs and the cyp51A gene is a hotspot for mutations that confer azole resistance. The most common cyp51A modifications could be grouped into two categories: A. fumigatus strains that harbor cyp51A single point mutations (G54, G138, M220, or G448) [ 47 , 48 , 49 , 50 ], and isolates with specific point mutations in cyp51A gene together with various size tandem repeat (TR) integrations in the promoter of the gene (TR34/L98H, TR34/L98H/S297T/F495I, TR46/Y121F/T289A, or TR53) [ 24 , 51 , 52 , 53 ]. Moreover, all these cyp51A modifications have been described to evolve from two different azole resistance acquisition routes: the first set of strains come from the clinical setting as a consequence of the in-host drug adaptation after azole exposure in the patient [ 54 ], while the second set of isolates with TR insertions are hypothesized to develop from the azole exposure in the environmental setting [ 13 , 37 , 55 , 56 , 57 , 58 ].…”

Comparison of Two Highly Discriminatory Typing Methods to Analyze Aspergillus fumigatus Azole Resistance

“…However, this result was not obtained using STR Af assay, where TR azole resistant strains were distributed in three different clusters (Supplementary Figure S2 ). Similarly, some authors have described this dispersed structure in the TR azole resistant A. fumigatus population using STR Af as genotyping method ( Ashu et al, 2017 ; Chen et al, 2018 ), although in some studies this may be due to the lack of differentiation between azole resistance mechanisms ( Ashu et al, 2017 ).…”