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Candida albicans gains azole resistance by altering sphingolipid composition

Fungal infections by drug-resistant Candida albicans pose a global public health threat. However, the pathogen’s diploid genome greatly hinders genome-wide investigations of resistance mechanisms. Here, we develop an efficient piggyBac transposon-mediated mutagenesis system using stable haploid C. a...

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Autores principales: Gao, Jiaxin, Wang, Haitao, Li, Zeyao, Wong, Ada Hang-Heng, Wang, Yi-Zheng, Guo, Yahui, Lin, Xin, Zeng, Guisheng, Liu, Haoping, Wang, Yue, Wang, Jianbin
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Nature Publishing Group UK 2018
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6206040/
https://www.ncbi.nlm.nih.gov/pubmed/30374049
http://dx.doi.org/10.1038/s41467-018-06944-1
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author Gao, Jiaxin
Wang, Haitao
Li, Zeyao
Wong, Ada Hang-Heng
Wang, Yi-Zheng
Guo, Yahui
Lin, Xin
Zeng, Guisheng
Liu, Haoping
Wang, Yue
Wang, Jianbin
author_facet Gao, Jiaxin
Wang, Haitao
Li, Zeyao
Wong, Ada Hang-Heng
Wang, Yi-Zheng
Guo, Yahui
Lin, Xin
Zeng, Guisheng
Liu, Haoping
Wang, Yue
Wang, Jianbin
author_sort Gao, Jiaxin
collection PubMed
description Fungal infections by drug-resistant Candida albicans pose a global public health threat. However, the pathogen’s diploid genome greatly hinders genome-wide investigations of resistance mechanisms. Here, we develop an efficient piggyBac transposon-mediated mutagenesis system using stable haploid C. albicans to conduct genome-wide genetic screens. We find that null mutants in either gene FEN1 or FEN12 (encoding enzymes for the synthesis of very-long-chain fatty acids as precursors of sphingolipids) exhibit resistance to fluconazole, a first-line antifungal drug. Mass-spectrometry analyses demonstrate changes in cellular sphingolipid composition in both mutants, including substantially increased levels of several mannosylinositolphosphoceramides with shorter fatty-acid chains. Treatment with fluconazole induces similar changes in wild-type cells, suggesting a natural response mechanism. Furthermore, the resistance relies on a robust upregulation of sphingolipid biosynthesis genes. Our results shed light into the mechanisms underlying azole resistance, and the new transposon-mediated mutagenesis system should facilitate future genome-wide studies of C. albicans.
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spelling pubmed-62060402018-10-31 Candida albicans gains azole resistance by altering sphingolipid composition Gao, Jiaxin Wang, Haitao Li, Zeyao Wong, Ada Hang-Heng Wang, Yi-Zheng Guo, Yahui Lin, Xin Zeng, Guisheng Liu, Haoping Wang, Yue Wang, Jianbin Nat Commun Article Fungal infections by drug-resistant Candida albicans pose a global public health threat. However, the pathogen’s diploid genome greatly hinders genome-wide investigations of resistance mechanisms. Here, we develop an efficient piggyBac transposon-mediated mutagenesis system using stable haploid C. albicans to conduct genome-wide genetic screens. We find that null mutants in either gene FEN1 or FEN12 (encoding enzymes for the synthesis of very-long-chain fatty acids as precursors of sphingolipids) exhibit resistance to fluconazole, a first-line antifungal drug. Mass-spectrometry analyses demonstrate changes in cellular sphingolipid composition in both mutants, including substantially increased levels of several mannosylinositolphosphoceramides with shorter fatty-acid chains. Treatment with fluconazole induces similar changes in wild-type cells, suggesting a natural response mechanism. Furthermore, the resistance relies on a robust upregulation of sphingolipid biosynthesis genes. Our results shed light into the mechanisms underlying azole resistance, and the new transposon-mediated mutagenesis system should facilitate future genome-wide studies of C. albicans. Nature Publishing Group UK 2018-10-29 /pmc/articles/PMC6206040/ /pubmed/30374049 http://dx.doi.org/10.1038/s41467-018-06944-1 Text en © The Author(s) 2018 Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/.
spellingShingle Article
Gao, Jiaxin
Wang, Haitao
Li, Zeyao
Wong, Ada Hang-Heng
Wang, Yi-Zheng
Guo, Yahui
Lin, Xin
Zeng, Guisheng
Liu, Haoping
Wang, Yue
Wang, Jianbin
Candida albicans gains azole resistance by altering sphingolipid composition
title Candida albicans gains azole resistance by altering sphingolipid composition
title_full Candida albicans gains azole resistance by altering sphingolipid composition
title_fullStr Candida albicans gains azole resistance by altering sphingolipid composition
title_full_unstemmed Candida albicans gains azole resistance by altering sphingolipid composition
title_short Candida albicans gains azole resistance by altering sphingolipid composition
title_sort candida albicans gains azole resistance by altering sphingolipid composition
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6206040/
https://www.ncbi.nlm.nih.gov/pubmed/30374049
http://dx.doi.org/10.1038/s41467-018-06944-1
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