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

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dos Reis, Thaila Fernanda ; de Castro, Patricia Alves ; Bastos, Rafael Wesley ; Pinzan, Camila Figueiredo ; Souza, Pedro F. N. ; Ackloo, Suzanne ; Hossain, Mohammad Anwar ; Drewry, David Harold ; Alkhazraji, Sondus ; Ibrahim, Ashraf S. ; Jo, Hyunil ; Lightfoot, Jorge D. ; Adams, Emily M. ; Fuller, Kevin K. ; deGrado, William F. ; Goldman, Gustavo H.

• Tipo de documento: Artigo Científico
• Fonte: NATURE COMMUNICATIONS; v. 14, n. 1, p. 19-pg., 2023-04-12.

Resumo

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. 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. (AU)

• Processo FAPESP: 21/04977-5 - A identificação de vias metabólicas e compostos químicos que podem potenciar a ação de caspofungin contra Aspergillus fumigatus
• Beneficiário: Gustavo Henrique Goldman
• Modalidade de apoio: Auxílio à Pesquisa - Temático
• Processo FAPESP: 16/07870-9 - A influência de proteínas quinases ativadas por mitógenos (MAPK) na expressão de determinantes genéticos importantes para a virulência de Aspergillus fumigatus
• Beneficiário: Gustavo Henrique Goldman
• Modalidade de apoio: Auxílio à Pesquisa - Temático