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Candida albicans gains azole resistance by altering sphingolipid composition
Gao J.1; Wang H.2; Li Z.1; Wong A.H.-H.2; Wang Y.-Z.1; Guo Y.1; Lin X.1; Zeng G.3; Wang Y.3; Wang J.1
2018-12-01
Source PublicationNature Communications
ISSN20411723
Volume9Issue:1
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.

DOI10.1038/s41467-018-06944-1
URLView the original
Indexed BySCIE
Language英语
WOS Research AreaScience & Technology - Other Topics
WOS SubjectMultidisciplinary Sciences
WOS IDWOS:000448575400004
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Cited Times [WOS]:14   [WOS Record]     [Related Records in WOS]
Document TypeJournal article
CollectionFaculty of Health Sciences
Affiliation1.Tsinghua University
2.Universidade de Macau
3.A-Star, Institute of Molecular and Cell Biology
4.Yong Loo Lin School of Medicine
Recommended Citation
GB/T 7714
Gao J.,Wang H.,Li Z.,et al. Candida albicans gains azole resistance by altering sphingolipid composition[J]. Nature Communications,2018,9(1).
APA Gao J..,Wang H..,Li Z..,Wong A.H.-H..,Wang Y.-Z..,...&Wang J..(2018).Candida albicans gains azole resistance by altering sphingolipid composition.Nature Communications,9(1).
MLA Gao J.,et al."Candida albicans gains azole resistance by altering sphingolipid composition".Nature Communications 9.1(2018).
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