Colistin enhances caspofungin antifungal efficacy against Aspergillus fumigatus by modulating calcium homeostasis and stress responses
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.
Authors
- Thaila Fernanda dos Reis (ORCID: https://orcid.org/0000-0002-7776-977X)
- Patrícia Alves de Castro (ORCID: https://orcid.org/0000-0003-3045-6511)
- Xingyue Li (ORCID: https://orcid.org/0009-0000-4455-7802)
- Iran Malavazi (ORCID: https://orcid.org/0000-0002-4526-4961)
- Sara Fallah (ORCID: https://orcid.org/0009-0002-1755-2656)
- Charles Boone (ORCID: https://orcid.org/0000-0002-3542-6760)
- Nicole Robbins (ORCID: https://orcid.org/0000-0003-2821-9269)
- Gustavo H. Goldman (ORCID: https://orcid.org/0000-0002-2986-350X)
- Ling Lü (ORCID: https://orcid.org/0000-0002-2891-7326)
- Laura García Carnero
- Luis Alberto Vega Isuhuaylas (ORCID: https://orcid.org/0000-0001-7754-6843)
- Leah E. Cowen (ORCID: https://orcid.org/0000-0001-5797-0110)
- Jonatas Erick Maimoni Campanella (ORCID: https://orcid.org/0000-0001-5858-7041)
- Yoko Yashiroda (ORCID: https://orcid.org/0000-0003-3279-141X)
- Nir Osherov (ORCID: https://orcid.org/0000-0002-0433-0096)
- Camila Figueiredo Pinzan (ORCID: https://orcid.org/0000-0001-7635-2107)
- Mami Yoshimura
- Taylor Davie
Institutions
- Universidade de Ribeirão Preto (BR)
- Nanjing Normal University (CN)
- Tel Aviv University (IL)
- Universidade Federal de São Carlos (BR)
- Universidade de São Paulo (BR)
- University of Toronto (CA)
- RIKEN Center for Sustainable Resource Science (JP)
- Nanjing Drum Tower Hospital (CN)
- National Institute of Science and Technology (ID)
Publication Details
- Journal
- Nature Communications
- Published
- 2025-07-01
- DOI
- https://doi.org/10.1038/s41467-025-60991-z
- Citations
- 1
- Primary Topic
- Antifungal resistance and susceptibility
- Type
- article
- Field-Weighted Citation Impact
- 1.40
Funders
- GlaxoSmithKline
- Canadian Institute for Advanced Research
- LifeArc
- International Development Research Centre
- Ministry of Education, Culture, Sports, Science and Technology
- Fundação de Amparo à Pesquisa do Estado de São Paulo
- National Natural Science Foundation of China
- Coordenação de Aperfeiçoamento de Pessoal de Nível Superior
- Conselho Nacional de Desenvolvimento Científico e Tecnológico
- Azrieli Foundation
- National Institutes of Health
- Canadian Institutes of Health Research
- RIKEN
- National Institute of Allergy and Infectious Diseases