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Uncovering New Mutations Conferring Azole Resistance in the Aspergillus fumigatus cyp51A Gene

The opportunistic pathogen Aspergillus fumigatus has developed worldwide resistance to azoles largely through mutations in cytochromeP450 enzyme Cyp51. In this study, we indicated that in vitro azole situation results in emergence of azole-resistant mutations. There are previously identified azole-r...

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Autores principales: Chen, Peiying, Liu, Musang, Zeng, Qiuqiong, Zhang, Zheng, Liu, Weida, Sang, Hong, Lu, Ling
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Frontiers Media S.A. 2020
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6986205/
https://www.ncbi.nlm.nih.gov/pubmed/32038564
http://dx.doi.org/10.3389/fmicb.2019.03127
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author Chen, Peiying
Liu, Musang
Zeng, Qiuqiong
Zhang, Zheng
Liu, Weida
Sang, Hong
Lu, Ling
author_facet Chen, Peiying
Liu, Musang
Zeng, Qiuqiong
Zhang, Zheng
Liu, Weida
Sang, Hong
Lu, Ling
author_sort Chen, Peiying
collection PubMed
description The opportunistic pathogen Aspergillus fumigatus has developed worldwide resistance to azoles largely through mutations in cytochromeP450 enzyme Cyp51. In this study, we indicated that in vitro azole situation results in emergence of azole-resistant mutations. There are previously identified azole-resistant cyp51A mutations (M220K, M220I, M220R, G54E and G54W mutations) and we successfully identified in this study two new mutations (N248K/V436A, Y433N substitution) conferring azole resistance among 18 independent stable azole-resistant isolates. The Galleria mellonella model of A. fumigatus infection experiment verified that Cyp51A mutations N248K/V436A and Y433N reduce efficacy of azole therapy. In addition, a predicted Cyp51A 3D structural model suggested that Y433N mutation causes the reduced affinities between drug target Cyp51A and azole antifungals. This study suggests that drug selection pressure make it possible to isolate unidentified cyp51A mutations conferring azole resistance in A. fumigatus.
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spelling pubmed-69862052020-02-07 Uncovering New Mutations Conferring Azole Resistance in the Aspergillus fumigatus cyp51A Gene Chen, Peiying Liu, Musang Zeng, Qiuqiong Zhang, Zheng Liu, Weida Sang, Hong Lu, Ling Front Microbiol Microbiology The opportunistic pathogen Aspergillus fumigatus has developed worldwide resistance to azoles largely through mutations in cytochromeP450 enzyme Cyp51. In this study, we indicated that in vitro azole situation results in emergence of azole-resistant mutations. There are previously identified azole-resistant cyp51A mutations (M220K, M220I, M220R, G54E and G54W mutations) and we successfully identified in this study two new mutations (N248K/V436A, Y433N substitution) conferring azole resistance among 18 independent stable azole-resistant isolates. The Galleria mellonella model of A. fumigatus infection experiment verified that Cyp51A mutations N248K/V436A and Y433N reduce efficacy of azole therapy. In addition, a predicted Cyp51A 3D structural model suggested that Y433N mutation causes the reduced affinities between drug target Cyp51A and azole antifungals. This study suggests that drug selection pressure make it possible to isolate unidentified cyp51A mutations conferring azole resistance in A. fumigatus. Frontiers Media S.A. 2020-01-21 /pmc/articles/PMC6986205/ /pubmed/32038564 http://dx.doi.org/10.3389/fmicb.2019.03127 Text en Copyright © 2020 Chen, Liu, Zeng, Zhang, Liu, Sang and Lu. http://creativecommons.org/licenses/by/4.0/ This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.
spellingShingle Microbiology
Chen, Peiying
Liu, Musang
Zeng, Qiuqiong
Zhang, Zheng
Liu, Weida
Sang, Hong
Lu, Ling
Uncovering New Mutations Conferring Azole Resistance in the Aspergillus fumigatus cyp51A Gene
title Uncovering New Mutations Conferring Azole Resistance in the Aspergillus fumigatus cyp51A Gene
title_full Uncovering New Mutations Conferring Azole Resistance in the Aspergillus fumigatus cyp51A Gene
title_fullStr Uncovering New Mutations Conferring Azole Resistance in the Aspergillus fumigatus cyp51A Gene
title_full_unstemmed Uncovering New Mutations Conferring Azole Resistance in the Aspergillus fumigatus cyp51A Gene
title_short Uncovering New Mutations Conferring Azole Resistance in the Aspergillus fumigatus cyp51A Gene
title_sort uncovering new mutations conferring azole resistance in the aspergillus fumigatus cyp51a gene
topic Microbiology
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6986205/
https://www.ncbi.nlm.nih.gov/pubmed/32038564
http://dx.doi.org/10.3389/fmicb.2019.03127
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