A host defense peptide mimetic, brilacidin, potentiates caspofungin antifungal activity against human pathogenic fungi
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 (CA...
| Main Authors: | , , , , , , , , , , , , , , , |
|---|---|
| Format: | Article |
| Language: | English |
| Published: |
Nature Portfolio
2023-04-01
|
| Series: | Nature Communications |
| Online Access: | https://doi.org/10.1038/s41467-023-37573-y |
| _version_ | 1827966266712784896 |
|---|---|
| author | 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 |
| author_facet | 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 |
| author_sort | Thaila Fernanda dos Reis |
| collection | DOAJ |
| description | 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. |
| first_indexed | 2024-04-09T17:46:16Z |
| format | Article |
| id | doaj.art-95f2a58a934d446abc7358a90c1dec91 |
| institution | Directory Open Access Journal |
| issn | 2041-1723 |
| language | English |
| last_indexed | 2024-04-09T17:46:16Z |
| publishDate | 2023-04-01 |
| publisher | Nature Portfolio |
| record_format | Article |
| series | Nature Communications |
| spelling | doaj.art-95f2a58a934d446abc7358a90c1dec912023-04-16T11:18:30ZengNature PortfolioNature Communications2041-17232023-04-0114111910.1038/s41467-023-37573-yA host defense peptide mimetic, brilacidin, potentiates caspofungin antifungal activity against human pathogenic fungiThaila Fernanda dos Reis0Patrícia Alves de Castro1Rafael Wesley Bastos2Camila Figueiredo Pinzan3Pedro F. N. Souza4Suzanne Ackloo5Mohammad Anwar Hossain6David Harold Drewry7Sondus Alkhazraji8Ashraf S. Ibrahim9Hyunil Jo10Jorge D. Lightfoot11Emily M. Adams12Kevin K. Fuller13William F. deGrado14Gustavo H. Goldman15Faculdade de Ciências Farmacêuticas de Ribeirão Preto, Universidade de São PauloFaculdade de Ciências Farmacêuticas de Ribeirão Preto, Universidade de São PauloFaculdade de Ciências Farmacêuticas de Ribeirão Preto, Universidade de São PauloFaculdade de Ciências Farmacêuticas de Ribeirão Preto, Universidade de São PauloVisiting professor at Drug Research and Development Center, Department of Physiology and Pharmacology, Federal University of CearáStructural Genomics Consortium, University of TorontoStructural Genomics Consortium, UNC Eshelman School of Pharmacy, University of North Carolina at Chapel HillStructural Genomics Consortium, UNC Eshelman School of Pharmacy, University of North Carolina at Chapel HillDivision of Infectious Diseases, The Lundquist Institute for Biomedical Innovation at Harbor-University of California Los Angeles (UCLA) Medical CenterDivision of Infectious Diseases, The Lundquist Institute for Biomedical Innovation at Harbor-University of California Los Angeles (UCLA) Medical CenterDepartment of Pharmaceutical Chemistry, University of California, San FranciscoDepartment of Ophthalmology, University of Oklahoma Health Sciences CenterDepartment of Ophthalmology, University of Oklahoma Health Sciences CenterDepartment of Ophthalmology, University of Oklahoma Health Sciences CenterDepartment of Pharmaceutical Chemistry, University of California, San FranciscoFaculdade de Ciências Farmacêuticas de Ribeirão Preto, Universidade de São PauloAbstract 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.https://doi.org/10.1038/s41467-023-37573-y |
| spellingShingle | 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 A host defense peptide mimetic, brilacidin, potentiates caspofungin antifungal activity against human pathogenic fungi Nature Communications |
| title | A host defense peptide mimetic, brilacidin, potentiates caspofungin antifungal activity against human pathogenic fungi |
| title_full | A host defense peptide mimetic, brilacidin, potentiates caspofungin antifungal activity against human pathogenic fungi |
| title_fullStr | A host defense peptide mimetic, brilacidin, potentiates caspofungin antifungal activity against human pathogenic fungi |
| title_full_unstemmed | A host defense peptide mimetic, brilacidin, potentiates caspofungin antifungal activity against human pathogenic fungi |
| title_short | A host defense peptide mimetic, brilacidin, potentiates caspofungin antifungal activity against human pathogenic fungi |
| title_sort | host defense peptide mimetic brilacidin potentiates caspofungin antifungal activity against human pathogenic fungi |
| url | https://doi.org/10.1038/s41467-023-37573-y |
| work_keys_str_mv | AT thailafernandadosreis ahostdefensepeptidemimeticbrilacidinpotentiatescaspofunginantifungalactivityagainsthumanpathogenicfungi AT patriciaalvesdecastro ahostdefensepeptidemimeticbrilacidinpotentiatescaspofunginantifungalactivityagainsthumanpathogenicfungi AT rafaelwesleybastos ahostdefensepeptidemimeticbrilacidinpotentiatescaspofunginantifungalactivityagainsthumanpathogenicfungi AT camilafigueiredopinzan ahostdefensepeptidemimeticbrilacidinpotentiatescaspofunginantifungalactivityagainsthumanpathogenicfungi AT pedrofnsouza ahostdefensepeptidemimeticbrilacidinpotentiatescaspofunginantifungalactivityagainsthumanpathogenicfungi AT suzanneackloo ahostdefensepeptidemimeticbrilacidinpotentiatescaspofunginantifungalactivityagainsthumanpathogenicfungi AT mohammadanwarhossain ahostdefensepeptidemimeticbrilacidinpotentiatescaspofunginantifungalactivityagainsthumanpathogenicfungi AT davidharolddrewry ahostdefensepeptidemimeticbrilacidinpotentiatescaspofunginantifungalactivityagainsthumanpathogenicfungi AT sondusalkhazraji ahostdefensepeptidemimeticbrilacidinpotentiatescaspofunginantifungalactivityagainsthumanpathogenicfungi AT ashrafsibrahim ahostdefensepeptidemimeticbrilacidinpotentiatescaspofunginantifungalactivityagainsthumanpathogenicfungi AT hyuniljo ahostdefensepeptidemimeticbrilacidinpotentiatescaspofunginantifungalactivityagainsthumanpathogenicfungi AT jorgedlightfoot ahostdefensepeptidemimeticbrilacidinpotentiatescaspofunginantifungalactivityagainsthumanpathogenicfungi AT emilymadams ahostdefensepeptidemimeticbrilacidinpotentiatescaspofunginantifungalactivityagainsthumanpathogenicfungi AT kevinkfuller ahostdefensepeptidemimeticbrilacidinpotentiatescaspofunginantifungalactivityagainsthumanpathogenicfungi AT williamfdegrado ahostdefensepeptidemimeticbrilacidinpotentiatescaspofunginantifungalactivityagainsthumanpathogenicfungi AT gustavohgoldman ahostdefensepeptidemimeticbrilacidinpotentiatescaspofunginantifungalactivityagainsthumanpathogenicfungi AT thailafernandadosreis hostdefensepeptidemimeticbrilacidinpotentiatescaspofunginantifungalactivityagainsthumanpathogenicfungi AT patriciaalvesdecastro hostdefensepeptidemimeticbrilacidinpotentiatescaspofunginantifungalactivityagainsthumanpathogenicfungi AT rafaelwesleybastos hostdefensepeptidemimeticbrilacidinpotentiatescaspofunginantifungalactivityagainsthumanpathogenicfungi AT camilafigueiredopinzan hostdefensepeptidemimeticbrilacidinpotentiatescaspofunginantifungalactivityagainsthumanpathogenicfungi AT pedrofnsouza hostdefensepeptidemimeticbrilacidinpotentiatescaspofunginantifungalactivityagainsthumanpathogenicfungi AT suzanneackloo hostdefensepeptidemimeticbrilacidinpotentiatescaspofunginantifungalactivityagainsthumanpathogenicfungi AT mohammadanwarhossain hostdefensepeptidemimeticbrilacidinpotentiatescaspofunginantifungalactivityagainsthumanpathogenicfungi AT davidharolddrewry hostdefensepeptidemimeticbrilacidinpotentiatescaspofunginantifungalactivityagainsthumanpathogenicfungi AT sondusalkhazraji hostdefensepeptidemimeticbrilacidinpotentiatescaspofunginantifungalactivityagainsthumanpathogenicfungi AT ashrafsibrahim hostdefensepeptidemimeticbrilacidinpotentiatescaspofunginantifungalactivityagainsthumanpathogenicfungi AT hyuniljo hostdefensepeptidemimeticbrilacidinpotentiatescaspofunginantifungalactivityagainsthumanpathogenicfungi AT jorgedlightfoot hostdefensepeptidemimeticbrilacidinpotentiatescaspofunginantifungalactivityagainsthumanpathogenicfungi AT emilymadams hostdefensepeptidemimeticbrilacidinpotentiatescaspofunginantifungalactivityagainsthumanpathogenicfungi AT kevinkfuller hostdefensepeptidemimeticbrilacidinpotentiatescaspofunginantifungalactivityagainsthumanpathogenicfungi AT williamfdegrado hostdefensepeptidemimeticbrilacidinpotentiatescaspofunginantifungalactivityagainsthumanpathogenicfungi AT gustavohgoldman hostdefensepeptidemimeticbrilacidinpotentiatescaspofunginantifungalactivityagainsthumanpathogenicfungi |