Open Access

Sterol uptake and sterol biosynthesis act coordinately to mediate antifungal resistance in Candida glabrata under azole and hypoxic stress

  • Authors:
    • Qingdi Quentin Li
    • Huei‑Fung Tsai
    • Ajeet Mandal
    • Bryan A. Walker
    • Jason A. Noble
    • Yuichi Fukuda
    • John E. Bennett
  • View Affiliations

  • Published online on: March 9, 2018     https://doi.org/10.3892/mmr.2018.8716
  • Pages: 6585-6597
  • Copyright: © Li et al. This is an open access article distributed under the terms of Creative Commons Attribution License.

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Abstract

Pathogenic fungi, including Candida glabrata, develop strategies to grow and survive both in vitro and in vivo under azole stress. However, the mechanisms by which yeast cells counteract the inhibitory effects of azoles are not completely understood. In the current study, it was demonstrated that the expression of the ergosterol biosynthetic genes ERG2, ERG3, ERG4, ERG10, and ERG11 was significantly upregulated in C. glabrata following fluconazole treatment. Inhibiting ergosterol biosynthesis using fluconazole also increased the expression of the sterol influx transporter AUS1 and the sterol metabolism regulators SUT1 and UPC2 in fungal cells. The microarray study quantified 35 genes with elevated mRNA levels, including AUS1, TIR3, UPC2, and 8 ERG genes, in a C. glabrata mutant strain lacking ERG1, indicating that sterol importing activity is increased to compensate for defective sterol biosynthesis in cells. Bioinformatic analyses further revealed that those differentially expressed genes were involved in multiple cellular processes and biological functions, such as sterol biosynthesis, lipid localization, and sterol transport. Finally, to assess whether sterol uptake affects yeast susceptibility to azoles, we generated a C. glabrata aus1∆ mutant strain. It was shown that loss of Aus1p in C. glabrata sensitized the pathogen to azoles and enhanced the efficacy of drug exposure under low oxygen tension. In contrast, the presence of exogenous cholesterol or ergosterol in medium rendered the C. glabrata AUS1 wild‑type strain highly resistant to fluconazole and voriconazole, suggesting that the sterol importing mechanism is augmented when ergosterol biosynthesis is suppressed in the cell, thus allowing C. glabrata to survive under azole pressure. On the basis of these results, it was concluded that sterol uptake and sterol biosynthesis may act coordinately and collaboratively to sustain growth and to mediate antifungal resistance in C. glabrata through dynamic gene expression in response to azole stress and environmental challenges.
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May-2018
Volume 17 Issue 5

Print ISSN: 1791-2997
Online ISSN:1791-3004

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Spandidos Publications style
Li QQ, Tsai HF, Mandal A, Walker BA, Noble JA, Fukuda Y and Bennett JE: Sterol uptake and sterol biosynthesis act coordinately to mediate antifungal resistance in Candida glabrata under azole and hypoxic stress. Mol Med Rep 17: 6585-6597, 2018
APA
Li, Q.Q., Tsai, H., Mandal, A., Walker, B.A., Noble, J.A., Fukuda, Y., & Bennett, J.E. (2018). Sterol uptake and sterol biosynthesis act coordinately to mediate antifungal resistance in Candida glabrata under azole and hypoxic stress. Molecular Medicine Reports, 17, 6585-6597. https://doi.org/10.3892/mmr.2018.8716
MLA
Li, Q. Q., Tsai, H., Mandal, A., Walker, B. A., Noble, J. A., Fukuda, Y., Bennett, J. E."Sterol uptake and sterol biosynthesis act coordinately to mediate antifungal resistance in Candida glabrata under azole and hypoxic stress". Molecular Medicine Reports 17.5 (2018): 6585-6597.
Chicago
Li, Q. Q., Tsai, H., Mandal, A., Walker, B. A., Noble, J. A., Fukuda, Y., Bennett, J. E."Sterol uptake and sterol biosynthesis act coordinately to mediate antifungal resistance in Candida glabrata under azole and hypoxic stress". Molecular Medicine Reports 17, no. 5 (2018): 6585-6597. https://doi.org/10.3892/mmr.2018.8716