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A host defense peptide mimetic, brilacidin, potentiates caspofungin antifungal activity against human pathogenic fungi

Author

Listed:
  • Thaila Fernanda Reis

    (Universidade de São Paulo)

  • Patrícia Alves Castro

    (Universidade de São Paulo)

  • Rafael Wesley Bastos

    (Universidade de São Paulo)

  • Camila Figueiredo Pinzan

    (Universidade de São Paulo)

  • Pedro F. N. Souza

    (Federal University of Ceará)

  • Suzanne Ackloo

    (University of Toronto)

  • Mohammad Anwar Hossain

    (University of North Carolina at Chapel Hill)

  • David Harold Drewry

    (University of North Carolina at Chapel Hill
    University of North Carolina at Chapel Hill)

  • Sondus Alkhazraji

    (The Lundquist Institute for Biomedical Innovation at Harbor-University of California Los Angeles (UCLA) Medical Center)

  • Ashraf S. Ibrahim

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

  • Hyunil Jo

    (University of California, San Francisco)

  • Jorge D. Lightfoot

    (University of Oklahoma Health Sciences Center)

  • Emily M. Adams

    (University of Oklahoma Health Sciences Center)

  • Kevin K. Fuller

    (University of Oklahoma Health Sciences Center
    Department of Microbiology and Immunology, University of Oklahoma Health Sciences Center)

  • William F. deGrado

    (University of California, San Francisco)

  • Gustavo H. Goldman

    (Universidade de São Paulo)

Abstract

Fungal infections cause more than 1.5 million deaths a year. Due to emerging antifungal drug resistance, novel strategies are urgently needed to combat life-threatening fungal diseases. Here, we identify the host defense peptide mimetic, brilacidin (BRI) as a synergizer with caspofungin (CAS) against CAS-sensitive and CAS-resistant isolates of Aspergillus fumigatus, Candida albicans, C. auris, and CAS-intrinsically resistant Cryptococcus neoformans. BRI also potentiates azoles against A. fumigatus and several Mucorales fungi. BRI acts in A. fumigatus by affecting cell wall integrity pathway and cell membrane potential. BRI combined with CAS significantly clears A. fumigatus lung infection in an immunosuppressed murine model of invasive pulmonary aspergillosis. BRI alone also decreases A. fumigatus fungal burden and ablates disease development in a murine model of fungal keratitis. Our results indicate that combinations of BRI and antifungal drugs in clinical use are likely to improve the treatment outcome of aspergillosis and other fungal infections.

Suggested Citation

  • 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.
    • Handle: RePEc:nat:natcom:v:14:y:2023:i:1:d:10.1038_s41467-023-37573-y
    DOI: 10.1038/s41467-023-37573-y
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    References listed on IDEAS

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    1. 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.
    2. Nicola Nosengo, 2016. "Can you teach old drugs new tricks?," Nature, Nature, vol. 534(7607), pages 314-316, June.
    3. Janette Reader & Mariëtte E. van der Watt & Dale Taylor & Claire Le Manach & Nimisha Mittal & Sabine Ottilie & Anjo Theron & Phanankosi Moyo & Erica Erlank & Luisa Nardini & Nelius Venter & Sonja Laut, 2021. "Multistage and transmission-blocking targeted antimalarials discovered from the open-source MMV Pandemic Response Box," Nature Communications, Nature, vol. 12(1), pages 1-15, December.
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