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Impairing the interaction between Erg11 and cytochrome P450 reductase Ncp1 enhances azoles’ antifungal activities

Author

Listed:
  • Wanqian Li

    (Tongji University)

  • Malcolm Whiteway

    (Concordia University)

  • Sijin Hang

    (Tongji University)

  • Jinhua Yu

    (Tongji University)

  • Hui Lu

    (Tongji University)

  • Yuanying Jiang

    (Tongji University)

Abstract

Azole effectiveness against candidiasis can be compromised by Candida albicans resistance and tolerance, and unfortunately, few clinically useful compounds can enhance azole antifungal activities. We find that the amino acids V234, F235 and L238 of Erg11 are critical for its interaction with Ncp1, and the Ncp1-Erg11 association is important in azole response. Ellipticine and its analog phiKan 083 block this Erg11-Ncp1 interaction by targeting Ncp1, and boost antifungal effects of fluconazole in vitro and in vivo. A series of steps influencing this process—an initial elevation in reactive oxygen species, leading to protein oxidation and misfolding in the endoplasmic reticulum (ER) that causes ER stress. This stress leads to Ca2+ release from the ER, mitochondrial Ca2+ accumulation and dysfunction, increased ROS production, and apoptosis of C. albicans cells. Overall, disrupting the Erg11-Ncp1 interaction in C. albicans can serve as a useful approach to enhancing the antifungal properties of azoles.

Suggested Citation

  • Wanqian Li & Malcolm Whiteway & Sijin Hang & Jinhua Yu & Hui Lu & Yuanying Jiang, 2025. "Impairing the interaction between Erg11 and cytochrome P450 reductase Ncp1 enhances azoles’ antifungal activities," Nature Communications, Nature, vol. 16(1), pages 1-18, December.
    • Handle: RePEc:nat:natcom:v:16:y:2025:i:1:d:10.1038_s41467-025-62131-z
    DOI: 10.1038/s41467-025-62131-z
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    References listed on IDEAS

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    1. Alexandros A. Pittis & Valerie Goh & Alberto Cebrian-Serrano & Jennifer Wettmarshausen & Fabiana Perocchi & Toni Gabaldón, 2020. "Discovery of EMRE in fungi resolves the true evolutionary history of the mitochondrial calcium uniporter," Nature Communications, Nature, vol. 11(1), pages 1-10, December.
    2. Alexander Rosenberg & Iuliana V. Ene & Maayan Bibi & Shiri Zakin & Ella Shtifman Segal & Naomi Ziv & Alon M. Dahan & Arnaldo Lopes Colombo & Richard J. Bennett & Judith Berman, 2018. "Antifungal tolerance is a subpopulation effect distinct from resistance and is associated with persistent candidemia," Nature Communications, Nature, vol. 9(1), pages 1-14, December.
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