2. Academic Validation
  3. Colistin enhances caspofungin antifungal efficacy against Aspergillus fumigatus by modulating calcium homeostasis and stress responses

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

  • Nat Commun. 2025 Jul 1;16(1):5967. doi: 10.1038/s41467-025-60991-z.
Laura Cristina García Carnero # 1,  Xingyue Li # 2,  Patrícia Alves de Castro 1,  Camila Figueiredo Pinzan 1,  Jonatas Erick Maimoni Campanella 3,  Iran Malavazi 3 4,  Mami Yoshimura 5,  Luis Alberto Vega Isuhuaylas 6,  Yoko Yashiroda 5,  Charles Boone 5 6 7,  Nir Osherov 8,  Sara Fallah 6,  Taylor Davie 6,  Nicole Robbins 6,  Leah Cowen 6,  Ling Lu 9,  Thaila Fernanda Dos Reis 10 11,  Gustavo H Goldman 12 13
Affiliations

Affiliations

  • 1 Faculdade de Ciências Farmacêuticas de Ribeirão Preto, Universidade de São Paulo, Ribeirão Preto, Brazil.
  • 2 Department of Clinical Laboratory, Nanjing Drum Tower Hospital, College of Life Science, Nanjing Normal University, Nanjing, Jiangsu, China.
  • 3 Departamento de Genética e Evolução, Centro de Ciências Biológicas e da Saúde, Universidade Federal de São Carlos, São Carlos, São Paulo, Brazil.
  • 4 National Institute of Science and Technology in Human Pathogenic Fungi, São Paulo, Brazil.
  • 5 RIKEN Center for Sustainable Resource Science, Wako, Saitama, Japan.
  • 6 Department of Molecular Genetics, University of Toronto, Toronto, ON, Canada.
  • 7 Donnelly Centre for Cellular and Biomolecular Research, University of Toronto, Toronto, ON, Canada.
  • 8 Department of Clinical Microbiology and Immunology, Sackler School of Medicine, Tel-Aviv University, Tel-Aviv, Israel.
  • 9 Department of Clinical Laboratory, Nanjing Drum Tower Hospital, College of Life Science, Nanjing Normal University, Nanjing, Jiangsu, China. linglu@njnu.edu.cn.
  • 10 Faculdade de Ciências Farmacêuticas de Ribeirão Preto, Universidade de São Paulo, Ribeirão Preto, Brazil. thailaf@hotmail.com.
  • 11 National Institute of Science and Technology in Human Pathogenic Fungi, São Paulo, Brazil. thailaf@hotmail.com.
  • 12 Faculdade de Ciências Farmacêuticas de Ribeirão Preto, Universidade de São Paulo, Ribeirão Preto, Brazil. ggoldman@usp.br.
  • 13 National Institute of Science and Technology in Human Pathogenic Fungi, São Paulo, Brazil. ggoldman@usp.br.
  • # Contributed equally.
PMID: 40592863 DOI: 10.1038/s41467-025-60991-z
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.

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