Gao, J., Wang, H., Li, Z. et al. Candida albicans gains azole resistance by altering sphingolipid composition. Nat Commun 9, 4495 (2018). https://doi.org/10.1038/s41467-018-06944-1
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.
This work was supported by the Thousand Young Talents Program (J.W.), Ministry of Science and Technology of China (2016YFC0900103 to J.W.), National Natural Science Foundation of China (21675098 to J.W.), THU-PKU Center for Life Sciences (J.G. and J.W.), and the Agency for Sciences, Technology and Research of Singapore (BMRC/BnB/0001b/2012 to Y.W.). Funding includes NIH GM117111 to H.L.