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

Thaila Fernanda Dos Reis; Patrícia Alves de 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; Gustavo H Goldman

doi:10.1038/s41467-023-37573-y

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

Nat Commun. 2023 Apr 12;14(1):2052. doi: 10.1038/s41467-023-37573-y.

Authors

Thaila Fernanda Dos Reis¹, Patrícia Alves de Castro¹, Rafael Wesley Bastos¹, Camila Figueiredo Pinzan¹, Pedro F N Souza², Suzanne Ackloo³, Mohammad Anwar Hossain⁴, David Harold Drewry^{4

5}, Sondus Alkhazraji⁶, Ashraf S Ibrahim^{6

7}, Hyunil Jo⁸, Jorge D Lightfoot⁹, Emily M Adams⁹, Kevin K Fuller^{9

10}, William F deGrado⁸, Gustavo H Goldman¹¹

Affiliations

¹ Faculdade de Ciências Farmacêuticas de Ribeirão Preto, Universidade de São Paulo, Ribeirão Preto, Brazil.
² Visiting professor at Drug Research and Development Center, Department of Physiology and Pharmacology, Federal University of Ceará, Fortaleza, Ceará, 60451, Brazil.
³ Structural Genomics Consortium, University of Toronto, 101 College Street, MaRS South Tower, Suite 700, Toronto, ON, M5G 1L7, Canada.
⁴ Structural Genomics Consortium, UNC Eshelman School of Pharmacy, University of North Carolina at Chapel Hill, Chapel Hill, NC, 27599, USA.
⁵ Lineberger Comprehensive Cancer Center, Department of Medicine, School of Medicine, University of North Carolina at Chapel Hill, Chapel Hill, NC, 27599, USA.
⁶ Division of Infectious Diseases, The Lundquist Institute for Biomedical Innovation at Harbor-University of California Los Angeles (UCLA) Medical Center, Torrance, CA, 90502, USA.
⁷ David Geffen School of Medicine at UCLA, Los Angeles, CA, 90095, USA.
⁸ Department of Pharmaceutical Chemistry, University of California, San Francisco, San Francisco, CA, 94143, USA.
⁹ Department of Ophthalmology, University of Oklahoma Health Sciences Center, Oklahoma City, OK, 73104, USA.
¹⁰ Department of Microbiology and Immunology, University of Oklahoma Health Sciences Center, Oklahoma City, OK, 73104, USA.
¹¹ Faculdade de Ciências Farmacêuticas de Ribeirão Preto, Universidade de São Paulo, Ribeirão Preto, Brazil. ggoldman@usp.br.

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.

Publication types

Research Support, Non-U.S. Gov't
Research Support, N.I.H., Extramural

MeSH terms

Animals
Antifungal Agents / pharmacology
Antifungal Agents / therapeutic use
Antimicrobial Cationic Peptides / therapeutic use
Aspergillosis* / microbiology
Aspergillus fumigatus
Candida albicans
Caspofungin / pharmacology
Caspofungin / therapeutic use
Disease Models, Animal
Drug Resistance, Fungal
Humans
Mice
Mycoses* / drug therapy

Substances

Antifungal Agents
Caspofungin
brilacidin
Antimicrobial Cationic Peptides

Abstract

Publication types

MeSH terms

Substances

Grants and funding