Candida albicans gains azole resistance by altering sphingolipid composition
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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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Transposon-based mutagenesis and disruption of C. albicans genome in a haploid strain identified potential genes involved in drug stress response.
“transposon-based mutagenesis and disruption of the C. albicans genome in a haploid strain identified a number of potential genes involved in drug stress response through Gene Set Enrichment Analysis”
From Molecular and genetic basis of azole antifungal resistance in the opportunistic pathogenic fungus<i>Candida albicans</i> (2020) · cites this paper as [195]
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- Authors
- Gao, J., Wang, H., Li, Z., Wong, A. H.-H., Wang, Y.-Z., Guo, Y., Lin, X., Zeng, G., Liu, H., Wang, Y., & Wang, J.
- Affiliations
- University of California, Irvine (US)
- Agency for Science, Technology and Research (SG)
- Tsinghua University (CN)
- University of Macau (MO)
- Center for Life Sciences (CN)
- Corresponding author
- Wang, Yi-Zheng
- Wang, Yue
- Wang, Jianbin
- ORCID
- Venue
- Nature Communications
- Published
- 2018-10-29
- Volume
- 9
- Issue
- 1
- Pages
- 4495-4495
- ISSN
- 2041-1723 (ISSN-L)
- PMC
- PMC6206040
- OpenAlex
- W2896788073
- Cited by
- 130
- References
- 67
- Citations by year
- 2026: 13 · 2025: 14 · 2024: 21 · 2023: 14 · 2022: 18 · 2021: 16 · 2020: 21 · 2019: 13
- FWCI
- 9.46
- Type
- journal article
- Language
- en
- Update notices
- correction (2019-01-15)
- Open access
- gold
- doi.org
- Locations
- Nature Communications (publishedVersion, cc-by)
- Europe PMC (PubMed Central) (publishedVersion, other-oa)
- PubMed Central (publishedVersion, cc-by)
- PubMed (publishedVersion)
- National University of Singapore (submittedVersion, cc-by)
- RePEc: Research Papers in Economics (submittedVersion)
- DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion)
- DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
- Funders
- National Natural Science Foundation of China (21675098, 2016YFC0900103)
- National Institutes of Health
- Biomedical Research Council
- National Institute of General Medical Sciences (R01GM117111)
- National Institute of Allergy and Infectious Diseases (R01AI099190)
- Topics
- Health Sciences › Medicine › Infectious Diseases › Antifungal resistance and susceptibility
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Fungal and yeast genetics research
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Sphingolipid Metabolism and Signaling
- Keywords
- Candida albicans, azole resistance, fluconazole resistance, sphingolipid biosynthesis, very long chain fatty acids, FEN1, haploid yeast, genome-wide screen, antifungal resistance, fungal infection
- MeSH terms
- Azoles, Base Sequence, Candida albicans, DNA Transposable Elements, Genes, Fungal, Genetic Testing, Haploidy, Mutation, Sphingolipids, Sterols, Mutagenesis, Drug Resistance, Fungal
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