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

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, Ashraf S. Ibrahim, Hyunil Jo, Jorge D. Lightfoot, Emily M. Adams, Kevin K. Fuller, William F. deGrado and Gustavo H. Goldman ()
Additional contact information
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
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
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
William F. deGrado: University of California, San Francisco
Gustavo H. Goldman: Universidade de São Paulo

Nature Communications, 2023, vol. 14, issue 1, 1-19

Abstract: 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.

Date: 2023
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DOI: 10.1038/s41467-023-37573-y

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