The Medical Triazole Voriconazole Can Select for Tandem Repeat Variations in Azole-Resistant <i>Aspergillus Fumigatus</i> Harboring TR<sub>34</sub>/L98H Via Asexual Reproduction
Azole-resistant <i>Aspergillus fumigatus</i> isolates recovered at high frequency from patients, harbor mutations that are associated with variation of promoter length in the <i>cyp51A</i> gene. Following the discovery of the TR<sub>34</sub>/L98H genotype, new var...
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doaj-fbb2a86ac60a46e4ba38182d467d37292020-11-25T04:06:14ZengMDPI AGJournal of Fungi2309-608X2020-11-01627727710.3390/jof6040277The Medical Triazole Voriconazole Can Select for Tandem Repeat Variations in Azole-Resistant <i>Aspergillus Fumigatus</i> Harboring TR<sub>34</sub>/L98H Via Asexual ReproductionJianhua Zhang0Jan Zoll1Tobias Engel2Joost van den Heuvel3Paul E. Verweij4Alfons J. M. Debets5Laboratory for Genetics, Wageningen University and Research, 6708 PB Wageningen, The NetherlandsDepartment of Medical Microbiology, Radboud University Medical Center, 6500 HB Nijmegen, The NetherlandsDepartment of Medical Microbiology, Radboud University Medical Center, 6500 HB Nijmegen, The NetherlandsLaboratory for Genetics, Wageningen University and Research, 6708 PB Wageningen, The NetherlandsDepartment of Medical Microbiology, Radboud University Medical Center, 6500 HB Nijmegen, The NetherlandsLaboratory for Genetics, Wageningen University and Research, 6708 PB Wageningen, The NetherlandsAzole-resistant <i>Aspergillus fumigatus</i> isolates recovered at high frequency from patients, harbor mutations that are associated with variation of promoter length in the <i>cyp51A</i> gene. Following the discovery of the TR<sub>34</sub>/L98H genotype, new variations in tandem repeat (TR) length and number of repeats were identified, as well as additional single nucleotide polymorphisms (SNPs) in the <i>cyp51A</i> gene, indicating that the diversity of resistance mutations in <i>A. fumigatus</i> is likely to continue to increase. Investigating the development routes of TR variants is critical to be able to design preventive interventions. In this study, we tested the potential effects of azole exposure on the selection of TR variations, while allowing haploid <i>A. fumigatus</i> to undergo asexual reproduction. Through experimental evolution involving voriconazole (VOR) exposure, an isolate harboring TR<sub>34</sub><sup>3</sup>/L98H evolved from a clinical TR<sub>34</sub>/L98H ancestor isolate, confirmed by whole genome sequencing. TR<sub>34</sub><sup>3</sup>/L98H was associated with increased <i>cyp51A</i> expression and high VOR and posaconazole MICs, although additional acquired SNPs could also have contributed to the highly azole-resistant phenotype. Exposure to medical azoles was found to select for TR<sub>34</sub><sup>3</sup>, thus supporting the possibility of in-host selection of TR<sub>34</sub> variants.https://www.mdpi.com/2309-608X/6/4/277azole resistancetandem repeats variantsasexual reproduction<i>Aspergillus fumigatus</i>antifungal agents |
collection |
DOAJ |
language |
English |
format |
Article |
sources |
DOAJ |
author |
Jianhua Zhang Jan Zoll Tobias Engel Joost van den Heuvel Paul E. Verweij Alfons J. M. Debets |
spellingShingle |
Jianhua Zhang Jan Zoll Tobias Engel Joost van den Heuvel Paul E. Verweij Alfons J. M. Debets The Medical Triazole Voriconazole Can Select for Tandem Repeat Variations in Azole-Resistant <i>Aspergillus Fumigatus</i> Harboring TR<sub>34</sub>/L98H Via Asexual Reproduction Journal of Fungi azole resistance tandem repeats variants asexual reproduction <i>Aspergillus fumigatus</i> antifungal agents |
author_facet |
Jianhua Zhang Jan Zoll Tobias Engel Joost van den Heuvel Paul E. Verweij Alfons J. M. Debets |
author_sort |
Jianhua Zhang |
title |
The Medical Triazole Voriconazole Can Select for Tandem Repeat Variations in Azole-Resistant <i>Aspergillus Fumigatus</i> Harboring TR<sub>34</sub>/L98H Via Asexual Reproduction |
title_short |
The Medical Triazole Voriconazole Can Select for Tandem Repeat Variations in Azole-Resistant <i>Aspergillus Fumigatus</i> Harboring TR<sub>34</sub>/L98H Via Asexual Reproduction |
title_full |
The Medical Triazole Voriconazole Can Select for Tandem Repeat Variations in Azole-Resistant <i>Aspergillus Fumigatus</i> Harboring TR<sub>34</sub>/L98H Via Asexual Reproduction |
title_fullStr |
The Medical Triazole Voriconazole Can Select for Tandem Repeat Variations in Azole-Resistant <i>Aspergillus Fumigatus</i> Harboring TR<sub>34</sub>/L98H Via Asexual Reproduction |
title_full_unstemmed |
The Medical Triazole Voriconazole Can Select for Tandem Repeat Variations in Azole-Resistant <i>Aspergillus Fumigatus</i> Harboring TR<sub>34</sub>/L98H Via Asexual Reproduction |
title_sort |
medical triazole voriconazole can select for tandem repeat variations in azole-resistant <i>aspergillus fumigatus</i> harboring tr<sub>34</sub>/l98h via asexual reproduction |
publisher |
MDPI AG |
series |
Journal of Fungi |
issn |
2309-608X |
publishDate |
2020-11-01 |
description |
Azole-resistant <i>Aspergillus fumigatus</i> isolates recovered at high frequency from patients, harbor mutations that are associated with variation of promoter length in the <i>cyp51A</i> gene. Following the discovery of the TR<sub>34</sub>/L98H genotype, new variations in tandem repeat (TR) length and number of repeats were identified, as well as additional single nucleotide polymorphisms (SNPs) in the <i>cyp51A</i> gene, indicating that the diversity of resistance mutations in <i>A. fumigatus</i> is likely to continue to increase. Investigating the development routes of TR variants is critical to be able to design preventive interventions. In this study, we tested the potential effects of azole exposure on the selection of TR variations, while allowing haploid <i>A. fumigatus</i> to undergo asexual reproduction. Through experimental evolution involving voriconazole (VOR) exposure, an isolate harboring TR<sub>34</sub><sup>3</sup>/L98H evolved from a clinical TR<sub>34</sub>/L98H ancestor isolate, confirmed by whole genome sequencing. TR<sub>34</sub><sup>3</sup>/L98H was associated with increased <i>cyp51A</i> expression and high VOR and posaconazole MICs, although additional acquired SNPs could also have contributed to the highly azole-resistant phenotype. Exposure to medical azoles was found to select for TR<sub>34</sub><sup>3</sup>, thus supporting the possibility of in-host selection of TR<sub>34</sub> variants. |
topic |
azole resistance tandem repeats variants asexual reproduction <i>Aspergillus fumigatus</i> antifungal agents |
url |
https://www.mdpi.com/2309-608X/6/4/277 |
work_keys_str_mv |
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