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Candida albicans gains azole resistance by altering sphingolipid composition

Author

Listed:
  • Jiaxin Gao

    (Tsinghua University
    Tsinghua University
    University of California)

  • Haitao Wang

    (University of Macau
    Agency for Science, Technology and Research)

  • Zeyao Li

    (Tsinghua University
    Tsinghua University)

  • Ada Hang-Heng Wong

    (University of Macau)

  • Yi-Zheng Wang

    (Tsinghua University)

  • Yahui Guo

    (Tsinghua University)

  • Xin Lin

    (Tsinghua University)

  • Guisheng Zeng

    (Agency for Science, Technology and Research)

  • Haoping Liu

    (University of California)

  • Yue Wang

    (Agency for Science, Technology and Research
    National University of Singapore)

  • Jianbin Wang

    (Tsinghua University
    Tsinghua University)

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.

Suggested Citation

  • Jiaxin Gao & Haitao Wang & Zeyao Li & Ada Hang-Heng Wong & Yi-Zheng Wang & Yahui Guo & Xin Lin & Guisheng Zeng & Haoping Liu & Yue Wang & Jianbin Wang, 2018. "Candida albicans gains azole resistance by altering sphingolipid composition," Nature Communications, Nature, vol. 9(1), pages 1-14, December.
    • Handle: RePEc:nat:natcom:v:9:y:2018:i:1:d:10.1038_s41467-018-06944-1
    DOI: 10.1038/s41467-018-06944-1
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    Cited by:

    1. Nicole M. Revie & Kali R. Iyer & Michelle E. Maxson & Jiabao Zhang & Su Yan & Caroline M. Fernandes & Kirsten J. Meyer & Xuefei Chen & Iwona Skulska & Meea Fogal & Hiram Sanchez & Saif Hossain & Sheen, 2022. "Targeting fungal membrane homeostasis with imidazopyrazoindoles impairs azole resistance and biofilm formation," Nature Communications, Nature, vol. 13(1), pages 1-20, December.
    2. Neil A. R. Gow & Carolyn Johnson & Judith Berman & Alix T. Coste & Christina A. Cuomo & David S. Perlin & Tihana Bicanic & Thomas S. Harrison & Nathan Wiederhold & Mike Bromley & Tom Chiller & Keegan , 2022. "The importance of antimicrobial resistance in medical mycology," Nature Communications, Nature, vol. 13(1), pages 1-12, December.

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