Colistin enhances caspofungin antifungal efficacy against Aspergillus fumigatus by modulating calcium homeostasis and stress responses
Abstract Fungal infections cause more than 2.5 million deaths a year. Due to emerging antifungal drug resistance, novel strategies are urgently needed to combat life-threatening fungal diseases. Here, by screening a collection of 5297 compounds derived from three chemical libraries, we demonstrate t...
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| Format: | Article |
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Nature Portfolio
2025-07-01
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| Series: | Nature Communications |
| Online Access: | https://doi.org/10.1038/s41467-025-60991-z |
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| author | Laura Cristina García Carnero Xingyue Li Patrícia Alves de Castro Camila Figueiredo Pinzan Jonatas Erick Maimoni Campanella Iran Malavazi Mami Yoshimura Luis Alberto Vega Isuhuaylas Yoko Yashiroda Charles Boone Nir Osherov Sara Fallah Taylor Davie Nicole Robbins Leah Cowen Ling Lu Thaila Fernanda dos Reis Gustavo H. Goldman |
| author_facet | Laura Cristina García Carnero Xingyue Li Patrícia Alves de Castro Camila Figueiredo Pinzan Jonatas Erick Maimoni Campanella Iran Malavazi Mami Yoshimura Luis Alberto Vega Isuhuaylas Yoko Yashiroda Charles Boone Nir Osherov Sara Fallah Taylor Davie Nicole Robbins Leah Cowen Ling Lu Thaila Fernanda dos Reis Gustavo H. Goldman |
| author_sort | Laura Cristina García Carnero |
| collection | DOAJ |
| description | Abstract Fungal infections cause more than 2.5 million deaths a year. Due to emerging antifungal drug resistance, novel strategies are urgently needed to combat life-threatening fungal diseases. Here, by screening a collection of 5297 compounds derived from three chemical libraries, we demonstrate that the antibacterial agent colistin (COL) can potentiate the fungistatic echinocandins caspofungin (CAS) and anidulafungin, as well as the structurally distinct cell wall targeting antifungal ibrexafungerp against Aspergillus fumigatus. Chemical and genetic screenings revealed that protein kinase C and the transcription factor SltA are involved in the mechanism of action of COL. SltA is essential for coping with calcium-limiting conditions, and the addition of calcium rescues COL-susceptibility. COL + CAS decreases A. fumigatus infection in human pulmonary cells, Galleria mellonella, and Caenorhabditis elegans. In summary, we demonstrate that the mechanism of COL as a synergizer of CAS against A. fumigatus is the disruption of the cell membrane permeability and calcium homeostasis. |
| format | Article |
| id | doaj-art-bffc0550cd4e4ea68d96a1ed42dbf1b4 |
| institution | Kabale University |
| issn | 2041-1723 |
| language | English |
| publishDate | 2025-07-01 |
| publisher | Nature Portfolio |
| record_format | Article |
| series | Nature Communications |
| spelling | doaj-art-bffc0550cd4e4ea68d96a1ed42dbf1b42025-08-20T04:03:13ZengNature PortfolioNature Communications2041-17232025-07-0116112310.1038/s41467-025-60991-zColistin enhances caspofungin antifungal efficacy against Aspergillus fumigatus by modulating calcium homeostasis and stress responsesLaura Cristina García Carnero0Xingyue Li1Patrícia Alves de Castro2Camila Figueiredo Pinzan3Jonatas Erick Maimoni Campanella4Iran Malavazi5Mami Yoshimura6Luis Alberto Vega Isuhuaylas7Yoko Yashiroda8Charles Boone9Nir Osherov10Sara Fallah11Taylor Davie12Nicole Robbins13Leah Cowen14Ling Lu15Thaila Fernanda dos Reis16Gustavo H. Goldman17Faculdade de Ciências Farmacêuticas de Ribeirão Preto, Universidade de São PauloDepartment of Clinical Laboratory, Nanjing Drum Tower Hospital, College of Life Science, Nanjing Normal UniversityFaculdade de Ciências Farmacêuticas de Ribeirão Preto, Universidade de São PauloFaculdade de Ciências Farmacêuticas de Ribeirão Preto, Universidade de São PauloDepartamento de Genética e Evolução, Centro de Ciências Biológicas e da Saúde, Universidade Federal de São CarlosDepartamento de Genética e Evolução, Centro de Ciências Biológicas e da Saúde, Universidade Federal de São CarlosRIKEN Center for Sustainable Resource ScienceDepartment of Molecular Genetics, University of TorontoRIKEN Center for Sustainable Resource ScienceRIKEN Center for Sustainable Resource ScienceDepartment of Clinical Microbiology and Immunology, Sackler School of Medicine, Tel-Aviv UniversityDepartment of Molecular Genetics, University of TorontoDepartment of Molecular Genetics, University of TorontoDepartment of Molecular Genetics, University of TorontoDepartment of Molecular Genetics, University of TorontoDepartment of Clinical Laboratory, Nanjing Drum Tower Hospital, College of Life Science, Nanjing Normal UniversityFaculdade de Ciências Farmacêuticas de Ribeirão Preto, Universidade de São PauloFaculdade de Ciências Farmacêuticas de Ribeirão Preto, Universidade de São PauloAbstract Fungal infections cause more than 2.5 million deaths a year. Due to emerging antifungal drug resistance, novel strategies are urgently needed to combat life-threatening fungal diseases. Here, by screening a collection of 5297 compounds derived from three chemical libraries, we demonstrate that the antibacterial agent colistin (COL) can potentiate the fungistatic echinocandins caspofungin (CAS) and anidulafungin, as well as the structurally distinct cell wall targeting antifungal ibrexafungerp against Aspergillus fumigatus. Chemical and genetic screenings revealed that protein kinase C and the transcription factor SltA are involved in the mechanism of action of COL. SltA is essential for coping with calcium-limiting conditions, and the addition of calcium rescues COL-susceptibility. COL + CAS decreases A. fumigatus infection in human pulmonary cells, Galleria mellonella, and Caenorhabditis elegans. In summary, we demonstrate that the mechanism of COL as a synergizer of CAS against A. fumigatus is the disruption of the cell membrane permeability and calcium homeostasis.https://doi.org/10.1038/s41467-025-60991-z |
| spellingShingle | Laura Cristina García Carnero Xingyue Li Patrícia Alves de Castro Camila Figueiredo Pinzan Jonatas Erick Maimoni Campanella Iran Malavazi Mami Yoshimura Luis Alberto Vega Isuhuaylas Yoko Yashiroda Charles Boone Nir Osherov Sara Fallah Taylor Davie Nicole Robbins Leah Cowen Ling Lu Thaila Fernanda dos Reis Gustavo H. Goldman Colistin enhances caspofungin antifungal efficacy against Aspergillus fumigatus by modulating calcium homeostasis and stress responses Nature Communications |
| title | Colistin enhances caspofungin antifungal efficacy against Aspergillus fumigatus by modulating calcium homeostasis and stress responses |
| title_full | Colistin enhances caspofungin antifungal efficacy against Aspergillus fumigatus by modulating calcium homeostasis and stress responses |
| title_fullStr | Colistin enhances caspofungin antifungal efficacy against Aspergillus fumigatus by modulating calcium homeostasis and stress responses |
| title_full_unstemmed | Colistin enhances caspofungin antifungal efficacy against Aspergillus fumigatus by modulating calcium homeostasis and stress responses |
| title_short | Colistin enhances caspofungin antifungal efficacy against Aspergillus fumigatus by modulating calcium homeostasis and stress responses |
| title_sort | colistin enhances caspofungin antifungal efficacy against aspergillus fumigatus by modulating calcium homeostasis and stress responses |
| url | https://doi.org/10.1038/s41467-025-60991-z |
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