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<p><i>Candida auris</i> is an emerging fungal pathogen notable for its intrinsically high resistance to fluconazole, the most prescribed antifungal drug. However, the genetic regulators underlying fluconazole susceptibility in <i>C. auris</i> remain unclear. Here we performed a pooled screen of <i>piggyBac</i> (<i>PB</i>) transposition mutants and identified significant enrichment of mitochondrial genes whose inactivation reduces fluconazole susceptibility. A genome-wide genetic interaction analysis of a mitochondrial gene deletion mutant, <i>pet309</i>Δ, suggests that the vacuolar calcium pump homologue <i>CDT1</i> (Calcium and Drug Transporter 1) is responsible for its reduced fluconazole susceptibility. Fluconazole induces significant upregulation of <i>CDT1</i> through the calcineurin signalling pathway. Cdt1, beyond its canonical calcium-pumping function, has evolved another function in mediating fluconazole efflux through its fluconazole-induced, calcineurin- and ATP hydrolysis-dependent plasma membrane localization. In addition, Cdt1 accelerates the evolution of fluconazole resistance or tolerance, and its transcript levels are substantially elevated across resistant clinical isolates. Our findings reveal a neofunctionalized role for Cdt1 in mediating fluconazole efflux in <i>C. auris</i>.</p>

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Candida auris vacuolar calcium pump mediates fluconazole efflux and resistance evolution

  • 期刊论文

  • 发表日期：

    2026年2月17日

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  • Yabing Song,
  • Jinxin Chen,
  • Junhua Wan,
  • Jiamo Zhang,
  • Qizheng Liu,
  • Fei Sun,
  • Hanlin Zhang,
  • Yuru Guo,
  • Eve W. L. Chow,
  • Yali Chen,
  • Ziyu Yan,
  • Jianbin Wang,
  • Kun Chen,
  • Yue Wang,
  • Jiaxin Gao

摘要

Candida auris is an emerging fungal pathogen notable for its intrinsically high resistance to fluconazole, the most prescribed antifungal drug. However, the genetic regulators underlying fluconazole susceptibility in C. auris remain unclear. Here we performed a pooled screen of piggyBac (PB) transposition mutants and identified significant enrichment of mitochondrial genes whose inactivation reduces fluconazole susceptibility. A genome-wide genetic interaction analysis of a mitochondrial gene deletion mutant, pet309Δ, suggests that the vacuolar calcium pump homologue CDT1 (Calcium and Drug Transporter 1) is responsible for its reduced fluconazole susceptibility. Fluconazole induces significant upregulation of CDT1 through the calcineurin signalling pathway. Cdt1, beyond its canonical calcium-pumping function, has evolved another function in mediating fluconazole efflux through its fluconazole-induced, calcineurin- and ATP hydrolysis-dependent plasma membrane localization. In addition, Cdt1 accelerates the evolution of fluconazole resistance or tolerance, and its transcript levels are substantially elevated across resistant clinical isolates. Our findings reveal a neofunctionalized role for Cdt1 in mediating fluconazole efflux in C. auris.