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.

Current treatment of fungal infections is threatened by emerging antifungal drug resistance. In this work, the authors explore the synergistic activity of a host defense peptide mimetic, brilacidin, with caspofungin against a panel of fungal strains.

Details

Title
A host defense peptide mimetic, brilacidin, potentiates caspofungin antifungal activity against human pathogenic fungi
Author
dos Reis, Thaila Fernanda 1 ; de Castro, Patrícia Alves 1 ; Bastos, Rafael Wesley 1 ; Pinzan, Camila Figueiredo 1 ; Souza, Pedro F. N. 2   VIAFID ORCID Logo  ; Ackloo, Suzanne 3   VIAFID ORCID Logo  ; Hossain, Mohammad Anwar 4   VIAFID ORCID Logo  ; Drewry, David Harold 5   VIAFID ORCID Logo  ; Alkhazraji, Sondus 6 ; Ibrahim, Ashraf S. 7   VIAFID ORCID Logo  ; Jo, Hyunil 8   VIAFID ORCID Logo  ; Lightfoot, Jorge D. 9 ; Adams, Emily M. 9   VIAFID ORCID Logo  ; Fuller, Kevin K. 10 ; deGrado, William F. 8 ; Goldman, Gustavo H. 1   VIAFID ORCID Logo 

1  Universidade de São Paulo, Faculdade de Ciências Farmacêuticas de Ribeirão Preto, Ribeirão Preto, Brazil (GRID:grid.11899.38) (ISNI:0000 0004 1937 0722) 
2  Federal University of Ceará, Visiting professor at Drug Research and Development Center, Department of Physiology and Pharmacology, Fortaleza, Brazil (GRID:grid.8395.7) (ISNI:0000 0001 2160 0329) 
3  University of Toronto, Structural Genomics Consortium, Toronto, Canada (GRID:grid.17063.33) (ISNI:0000 0001 2157 2938) 
4  University of North Carolina at Chapel Hill, Structural Genomics Consortium, UNC Eshelman School of Pharmacy, Chapel Hill, USA (GRID:grid.10698.36) (ISNI:0000000122483208) 
5  University of North Carolina at Chapel Hill, Structural Genomics Consortium, UNC Eshelman School of Pharmacy, Chapel Hill, USA (GRID:grid.10698.36) (ISNI:0000000122483208); University of North Carolina at Chapel Hill, Lineberger Comprehensive Cancer Center, Department of Medicine, School of Medicine, Chapel Hill, USA (GRID:grid.10698.36) (ISNI:0000000122483208) 
6  The Lundquist Institute for Biomedical Innovation at Harbor-University of California Los Angeles (UCLA) Medical Center, Division of Infectious Diseases, Torrance, USA (GRID:grid.513199.6) 
7  The Lundquist Institute for Biomedical Innovation at Harbor-University of California Los Angeles (UCLA) Medical Center, Division of Infectious Diseases, Torrance, USA (GRID:grid.513199.6); David Geffen School of Medicine at UCLA, Los Angeles, USA (GRID:grid.19006.3e) (ISNI:0000 0000 9632 6718) 
8  University of California, San Francisco, Department of Pharmaceutical Chemistry, San Francisco, USA (GRID:grid.266102.1) (ISNI:0000 0001 2297 6811) 
9  University of Oklahoma Health Sciences Center, Department of Ophthalmology, Oklahoma City, USA (GRID:grid.266902.9) (ISNI:0000 0001 2179 3618) 
10  University of Oklahoma Health Sciences Center, Department of Ophthalmology, Oklahoma City, USA (GRID:grid.266902.9) (ISNI:0000 0001 2179 3618); Department of Microbiology and Immunology, University of Oklahoma Health Sciences Center, Oklahoma City, USA (GRID:grid.266902.9) (ISNI:0000 0001 2179 3618) 
Pages
2052
Publication year
2023
Publication date
2023
Publisher
Nature Publishing Group
e-ISSN
20411723
Source type
Scholarly Journal
Language of publication
English
DOI
https://doi.org/10.1038/s41467-023-37573-y
ProQuest document ID
2799931697
Copyright
© The Author(s) 2023. This work is published under http://creativecommons.org/licenses/by/4.0/ (the “License”). Notwithstanding the ProQuest Terms and Conditions, you may use this content in accordance with the terms of the License.