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Colistin enhances caspofungin antifungal efficacy against Aspergillus fumigatus by modulating calcium homeostasis and stress responses

Author

Listed:
  • 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
    National Institute of Science and Technology in Human Pathogenic Fungi)

  • 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
    University of Toronto
    University of Toronto)

  • 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
    National Institute of Science and Technology in Human Pathogenic Fungi)

  • Gustavo H. Goldman

    (Universidade de São Paulo
    National Institute of Science and Technology in Human Pathogenic Fungi)

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.

Suggested Citation

  • 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 Yashir, 2025. "Colistin enhances caspofungin antifungal efficacy against Aspergillus fumigatus by modulating calcium homeostasis and stress responses," Nature Communications, Nature, vol. 16(1), pages 1-23, December.
    • Handle: RePEc:nat:natcom:v:16:y:2025:i:1:d:10.1038_s41467-025-60991-z
    DOI: 10.1038/s41467-025-60991-z
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