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Deletion of cox7c Results in Pan-Azole Resistance in Aspergillus fumigatus
In Aspergillus fumigatus, the most prevalent resistance to azoles results from mutational modifications of the azole target protein Cyp51A, but there are non-cyp51A mutants resistant to azoles, and the mechanisms underlying the resistance of these strains remain to be explored. Here, we identified a...
Autores principales: | , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
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American Society for Microbiology
2022
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Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9211413/ https://www.ncbi.nlm.nih.gov/pubmed/35647650 http://dx.doi.org/10.1128/aac.00151-22 |
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author | Chen, Mingcong Zhong, Guowei Wang, Sha Chen, Peiying Li, Lei |
author_facet | Chen, Mingcong Zhong, Guowei Wang, Sha Chen, Peiying Li, Lei |
author_sort | Chen, Mingcong |
collection | PubMed |
description | In Aspergillus fumigatus, the most prevalent resistance to azoles results from mutational modifications of the azole target protein Cyp51A, but there are non-cyp51A mutants resistant to azoles, and the mechanisms underlying the resistance of these strains remain to be explored. Here, we identified a novel cytochrome c oxidase, cox7c (W56*), nonsense mutation in the laboratory and found that it caused reduced colony growth and resistance to multiantifungal agents. Meanwhile, we revealed that cold storage is responsible for increased tolerance of conidia to itraconazole (ITC) stress, which further advances azole-resistant mutations (cryopreservation→ITC tolerance→azole resistance). The deletion or mutation of cox7c results explicitly in resistance to antifungal-targeting enzymes, including triazoles, polyenes, and allylamines, required for ergosterol synthesis, or resistance to fungal ergosterol. A high-performance liquid chromatography (HPLC) assay showed that the cox7c knockout strain decreased intracellular itraconazole concentration. In addition, the lack of Cox7c resulted in the accumulation of intracellular heme B. We validated that an endogenous increase in, or the exogenous addition of, heme B was capable of eliciting azole resistance, which was in good accordance with the phenotypic resistance analysis of cox7c mutants. Furthermore, RNA sequencing verified the elevated transcriptional expression levels of multidrug transport genes. Additionally, lower itraconazole-induced reactive oxygen species generation in mycelia of a cox7c-deletion strain suggested that this reduction may, in part, contribute to drug resistance. These findings increase our understanding of how A. fumigatus’s direct responses to azoles promote fungal survival in the environment and address genetic mutations that arise from patients or environments. |
format | Online Article Text |
id | pubmed-9211413 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2022 |
publisher | American Society for Microbiology |
record_format | MEDLINE/PubMed |
spelling | pubmed-92114132022-06-22 Deletion of cox7c Results in Pan-Azole Resistance in Aspergillus fumigatus Chen, Mingcong Zhong, Guowei Wang, Sha Chen, Peiying Li, Lei Antimicrob Agents Chemother Mechanisms of Resistance In Aspergillus fumigatus, the most prevalent resistance to azoles results from mutational modifications of the azole target protein Cyp51A, but there are non-cyp51A mutants resistant to azoles, and the mechanisms underlying the resistance of these strains remain to be explored. Here, we identified a novel cytochrome c oxidase, cox7c (W56*), nonsense mutation in the laboratory and found that it caused reduced colony growth and resistance to multiantifungal agents. Meanwhile, we revealed that cold storage is responsible for increased tolerance of conidia to itraconazole (ITC) stress, which further advances azole-resistant mutations (cryopreservation→ITC tolerance→azole resistance). The deletion or mutation of cox7c results explicitly in resistance to antifungal-targeting enzymes, including triazoles, polyenes, and allylamines, required for ergosterol synthesis, or resistance to fungal ergosterol. A high-performance liquid chromatography (HPLC) assay showed that the cox7c knockout strain decreased intracellular itraconazole concentration. In addition, the lack of Cox7c resulted in the accumulation of intracellular heme B. We validated that an endogenous increase in, or the exogenous addition of, heme B was capable of eliciting azole resistance, which was in good accordance with the phenotypic resistance analysis of cox7c mutants. Furthermore, RNA sequencing verified the elevated transcriptional expression levels of multidrug transport genes. Additionally, lower itraconazole-induced reactive oxygen species generation in mycelia of a cox7c-deletion strain suggested that this reduction may, in part, contribute to drug resistance. These findings increase our understanding of how A. fumigatus’s direct responses to azoles promote fungal survival in the environment and address genetic mutations that arise from patients or environments. American Society for Microbiology 2022-06-01 /pmc/articles/PMC9211413/ /pubmed/35647650 http://dx.doi.org/10.1128/aac.00151-22 Text en Copyright © 2022 Chen et al. https://creativecommons.org/licenses/by/4.0/This is an open-access article distributed under the terms of the Creative Commons Attribution 4.0 International license (https://creativecommons.org/licenses/by/4.0/) . |
spellingShingle | Mechanisms of Resistance Chen, Mingcong Zhong, Guowei Wang, Sha Chen, Peiying Li, Lei Deletion of cox7c Results in Pan-Azole Resistance in Aspergillus fumigatus |
title | Deletion of cox7c Results in Pan-Azole Resistance in Aspergillus fumigatus |
title_full | Deletion of cox7c Results in Pan-Azole Resistance in Aspergillus fumigatus |
title_fullStr | Deletion of cox7c Results in Pan-Azole Resistance in Aspergillus fumigatus |
title_full_unstemmed | Deletion of cox7c Results in Pan-Azole Resistance in Aspergillus fumigatus |
title_short | Deletion of cox7c Results in Pan-Azole Resistance in Aspergillus fumigatus |
title_sort | deletion of cox7c results in pan-azole resistance in aspergillus fumigatus |
topic | Mechanisms of Resistance |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9211413/ https://www.ncbi.nlm.nih.gov/pubmed/35647650 http://dx.doi.org/10.1128/aac.00151-22 |
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