Colistin enhances caspofungin antifungal efficacy against Aspergillus fumigatus by modulating calcium homeostasis and stress responses
Laura Garcia 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 () and
Gustavo H. Goldman ()
Additional contact information
Laura Garcia Carnero: Universidade de São Paulo
Xingyue Li: Nanjing Normal University
Patrícia Alves de Castro: Universidade de São Paulo
Camila Figueiredo Pinzan: Universidade de São Paulo
Jonatas Erick Maimoni Campanella: Universidade Federal de São Carlos
Iran Malavazi: Universidade Federal de São Carlos
Mami Yoshimura: RIKEN Center for Sustainable Resource Science
Luis Alberto Vega Isuhuaylas: University of Toronto
Yoko Yashiroda: RIKEN Center for Sustainable Resource Science
Charles Boone: RIKEN Center for Sustainable Resource Science
Nir Osherov: Tel-Aviv University
Sara Fallah: University of Toronto
Taylor Davie: University of Toronto
Nicole Robbins: University of Toronto
Leah Cowen: University of Toronto
Ling Lu: Nanjing Normal University
Thaila Fernanda dos Reis: Universidade de São Paulo
Gustavo H. Goldman: Universidade de São Paulo
Nature Communications, 2025, vol. 16, issue 1, 1-23
Abstract:
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.
Date: 2025
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Persistent link: https://EconPapers.repec.org/RePEc:nat:natcom:v:16:y:2025:i:1:d:10.1038_s41467-025-60991-z
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DOI: 10.1038/s41467-025-60991-z
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