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An oxindole efflux inhibitor potentiates azoles and impairs virulence in the fungal pathogen Candida auris

Author

Listed:
  • Kali R. Iyer

    (University of Toronto)

  • Kaddy Camara

    (Boston University
    Clark+Elbing LLP)

  • Martin Daniel-Ivad

    (University of Toronto)

  • Richard Trilles

    (Boston University)

  • Sheila M. Pimentel-Elardo

    (University of Toronto)

  • Jen L. Fossen

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

  • Karen Marchillo

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

  • Zhongle Liu

    (University of Toronto)

  • Shakti Singh

    (Division of Infectious Disease, The Lundquist Institute for Biomedical Innovation Los Angeles Biomedical Research Institute at Harbor-University of California, Los Angeles (UCLA) Medical Center)

  • José F. Muñoz

    (Infectious Disease and Microbiome Program, Broad Institute of MIT and Harvard)

  • Sang Hu Kim

    (University of Toronto)

  • John A. Porco

    (Boston University)

  • Christina A. Cuomo

    (Infectious Disease and Microbiome Program, Broad Institute of MIT and Harvard)

  • Noelle S. Williams

    (University of Texas Southwestern Medical School)

  • Ashraf S. Ibrahim

    (Division of Infectious Disease, The Lundquist Institute for Biomedical Innovation Los Angeles Biomedical Research Institute at Harbor-University of California, Los Angeles (UCLA) Medical Center
    David Geffen School of Medicine, UCLA)

  • John E. Edwards

    (Division of Infectious Disease, The Lundquist Institute for Biomedical Innovation Los Angeles Biomedical Research Institute at Harbor-University of California, Los Angeles (UCLA) Medical Center
    David Geffen School of Medicine, UCLA)

  • David R. Andes

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

  • Justin R. Nodwell

    (University of Toronto)

  • Lauren E. Brown

    (Boston University)

  • Luke Whitesell

    (University of Toronto)

  • Nicole Robbins

    (University of Toronto)

  • Leah E. Cowen

    (University of Toronto)

Abstract

Candida auris is an emerging fungal pathogen that exhibits resistance to multiple drugs, including the most commonly prescribed antifungal, fluconazole. Here, we use a combinatorial screening approach to identify a bis-benzodioxolylindolinone (azoffluxin) that synergizes with fluconazole against C. auris. Azoffluxin enhances fluconazole activity through the inhibition of efflux pump Cdr1, thus increasing intracellular fluconazole levels. This activity is conserved across most C. auris clades, with the exception of clade III. Azoffluxin also inhibits efflux in highly azole-resistant strains of Candida albicans, another human fungal pathogen, increasing their susceptibility to fluconazole. Furthermore, azoffluxin enhances fluconazole activity in mice infected with C. auris, reducing fungal burden. Our findings suggest that pharmacologically targeting Cdr1 in combination with azoles may be an effective strategy to control infection caused by azole-resistant isolates of C. auris.

Suggested Citation

  • Kali R. Iyer & Kaddy Camara & Martin Daniel-Ivad & Richard Trilles & Sheila M. Pimentel-Elardo & Jen L. Fossen & Karen Marchillo & Zhongle Liu & Shakti Singh & José F. Muñoz & Sang Hu Kim & John A. Po, 2020. "An oxindole efflux inhibitor potentiates azoles and impairs virulence in the fungal pathogen Candida auris," Nature Communications, Nature, vol. 11(1), pages 1-17, December.
    • Handle: RePEc:nat:natcom:v:11:y:2020:i:1:d:10.1038_s41467-020-20183-3
    DOI: 10.1038/s41467-020-20183-3
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    Cited by:

    1. Thaila Fernanda Reis & Patrícia Alves Castro & Rafael Wesley Bastos & Camila Figueiredo Pinzan & Pedro F. N. Souza & Suzanne Ackloo & Mohammad Anwar Hossain & David Harold Drewry & Sondus Alkhazraji &, 2023. "A host defense peptide mimetic, brilacidin, potentiates caspofungin antifungal activity against human pathogenic fungi," Nature Communications, Nature, vol. 14(1), pages 1-19, December.

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