Candida albicans gains azole resistance by altering sphingolipid composition

Jiaxin Gao, Haitao Wang, Zeyao Li, Ada Hang-Heng Wong, Yi-Zheng Wang, Yahui Guo, Xin Lin, Guisheng Zeng, Haoping Liu, Yue Wang () and Jianbin Wang ()
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Jiaxin Gao: Tsinghua University
Haitao Wang: University of Macau
Zeyao Li: 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
Jianbin Wang: Tsinghua University

Nature Communications, 2018, vol. 9, issue 1, 1-14

Abstract: 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.

Date: 2018
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DOI: 10.1038/s41467-018-06944-1

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