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Targeting fungal membrane homeostasis with imidazopyrazoindoles impairs azole resistance and biofilm formation

Author

Listed:
  • Nicole M. Revie

    (University of Toronto)

  • Kali R. Iyer

    (University of Toronto)

  • Michelle E. Maxson

    (The Hospital for Sick Children)

  • Jiabao Zhang

    (University of Illinois at Urbana-Champaign
    University of Illinois at Urbana-Champaign)

  • Su Yan

    (University of Illinois at Urbana-Champaign
    University of Illinois at Urbana-Champaign)

  • Caroline M. Fernandes

    (Stony Brook University)

  • Kirsten J. Meyer

    (University of Toronto)

  • Xuefei Chen

    (McMaster University)

  • Iwona Skulska

    (University of Guelph)

  • Meea Fogal

    (University of Guelph)

  • Hiram Sanchez

    (University of Wisconsin School of Medicine and Public Health
    University of Wisconsin)

  • Saif Hossain

    (University of Toronto)

  • Sheena Li

    (Donnelly Centre for Cellular and Biomolecular Research)

  • Yoko Yashiroda

    (RIKEN Center for Sustainable Resource Science, Wako)

  • Hiroyuki Hirano

    (RIKEN Center for Sustainable Resource Science, Wako)

  • Minoru Yoshida

    (RIKEN Center for Sustainable Resource Science, Wako
    The University of Tokyo
    The University of Tokyo)

  • Hiroyuki Osada

    (RIKEN Center for Sustainable Resource Science, Wako)

  • Charles Boone

    (Donnelly Centre for Cellular and Biomolecular Research
    RIKEN Center for Sustainable Resource Science, Wako)

  • Rebecca S. Shapiro

    (University of Guelph)

  • David R. Andes

    (University of Wisconsin School of Medicine and Public Health
    University of Wisconsin)

  • Gerard D. Wright

    (McMaster University)

  • Justin R. Nodwell

    (University of Toronto)

  • Maurizio Del Poeta

    (Stony Brook University
    Stony Brook University
    Veteran Administration Medical Center)

  • Martin D. Burke

    (University of Illinois at Urbana-Champaign
    University of Illinois at Urbana-Champaign
    University of Illinois at Urbana-Champaign
    University of Illinois at Urbana-Champaign)

  • Luke Whitesell

    (University of Toronto)

  • Nicole Robbins

    (University of Toronto)

  • Leah E. Cowen

    (University of Toronto)

Abstract

Fungal infections cause more than 1.5 million deaths annually. With an increase in immune-deficient susceptible populations and the emergence of antifungal drug resistance, there is an urgent need for novel strategies to combat these life-threatening infections. Here, we use a combinatorial screening approach to identify an imidazopyrazoindole, NPD827, that synergizes with fluconazole against azole-sensitive and -resistant isolates of Candida albicans. NPD827 interacts with sterols, resulting in profound effects on fungal membrane homeostasis and induction of membrane-associated stress responses. The compound impairs virulence in a Caenorhabditis elegans model of candidiasis, blocks C. albicans filamentation in vitro, and prevents biofilm formation in a rat model of catheter infection by C. albicans. Collectively, this work identifies an imidazopyrazoindole scaffold with a non-protein-targeted mode of action that re-sensitizes the leading human fungal pathogen, C. albicans, to azole antifungals.

Suggested Citation

  • Nicole M. Revie & Kali R. Iyer & Michelle E. Maxson & Jiabao Zhang & Su Yan & Caroline M. Fernandes & Kirsten J. Meyer & Xuefei Chen & Iwona Skulska & Meea Fogal & Hiram Sanchez & Saif Hossain & Sheen, 2022. "Targeting fungal membrane homeostasis with imidazopyrazoindoles impairs azole resistance and biofilm formation," Nature Communications, Nature, vol. 13(1), pages 1-20, December.
    • Handle: RePEc:nat:natcom:v:13:y:2022:i:1:d:10.1038_s41467-022-31308-1
    DOI: 10.1038/s41467-022-31308-1
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    References listed on IDEAS

    as
    1. Jiaxin Gao & Haitao Wang & Zeyao Li & Ada Hang-Heng Wong & Yi-Zheng Wang & Yahui Guo & Xin Lin & Guisheng Zeng & Haoping Liu & Yue Wang & Jianbin Wang, 2018. "Candida albicans gains azole resistance by altering sphingolipid composition," Nature Communications, Nature, vol. 9(1), pages 1-14, December.
    2. Teresa R. O’Meara & Amanda O. Veri & Troy Ketela & Bo Jiang & Terry Roemer & Leah E. Cowen, 2015. "Global analysis of fungal morphology exposes mechanisms of host cell escape," Nature Communications, Nature, vol. 6(1), pages 1-10, November.
    3. Losee L. Ling & Tanja Schneider & Aaron J. Peoples & Amy L. Spoering & Ina Engels & Brian P. Conlon & Anna Mueller & Till F. Schäberle & Dallas E. Hughes & Slava Epstein & Michael Jones & Linos Lazari, 2015. "A new antibiotic kills pathogens without detectable resistance," Nature, Nature, vol. 517(7535), pages 455-459, January.
    4. Losee L. Ling & Tanja Schneider & Aaron J. Peoples & Amy L. Spoering & Ina Engels & Brian P. Conlon & Anna Mueller & Till F. Schäberle & Dallas E. Hughes & Slava Epstein & Michael Jones & Linos Lazari, 2015. "Erratum: A new antibiotic kills pathogens without detectable resistance," Nature, Nature, vol. 520(7547), pages 388-388, April.
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