Cited by 130Antifungal resistance and susceptibilityFungal and yeast genetics researchSphingolipid Metabolism and Signaling

Candida albicans gains azole resistance by altering sphingolipid composition

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Gao, Jiaxin, Wang, Haitao, Li, Zeyao, Wong, Ada Hang-Heng, Wang, Yi-Zheng, Guo, Yahui, Lin, Xin, Zeng, Guisheng +3 more·2018·Nature Communications

Abstract

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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  1. [26]Jones, E. W. & Fink, G. R. Regulation of amino acid and nucleotide biosynthesis in yeast. In The Molecular Biology of the Yeast Saccharomyces: Metabolism and Gene Expression (eds Strathern, J. N. et al.) 181–299 (Cold Spring Harbor Laboratory Press, Cold Spring Harbor, NY, 1982).
  2. [67]Rex, J. H. et al. Clinical and Laboratory Standards Institute (CLSI). Reference Method for Broth Dilution Antifungal Susceptibility Testing of Yeasts, Approved Standard-Third Edition, CLSI document M27-A3 (ISBN 1-56238-666-2) (Clinical and Laboratory Standards Institute, 940 West Valley Road, Suite 1400, Wayne, Pennsylvania 19087-1898, USA, 2008).

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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
Venue
Nature Communications
Published
2018-10-29
Volume
9
Issue
1
Pages
4495-4495
ISSN
2041-1723 (ISSN-L)
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
Open access
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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