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

IF 15.7 1区综合性期刊 Q1 MULTIDISCIPLINARY SCIENCES

Nature Communications Pub Date : 2025-07-01 DOI:10.1038/s41467-025-60991-z

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, Gustavo H Goldman

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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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粘菌素通过调节钙稳态和应激反应增强caspofunins对烟曲霉的抗真菌效果。

真菌感染每年造成250多万人死亡。由于抗真菌药物耐药性的出现，迫切需要新的策略来对抗危及生命的真菌疾病。本研究通过筛选来自3个化学文库的5297个化合物，证明了抗菌药物粘菌素（colistin）可以增强抑菌剂棘白菌素caspofungin （CAS）和anidulafungin，以及结构独特的细胞壁靶向抗真菌药物ibrexafungerp对烟曲霉的抑制作用。化学和遗传筛选表明，蛋白激酶C和转录因子SltA参与了col的作用机制，SltA是应对钙限制条件的必要条件，钙的添加可以挽救col的易感性。COL + CAS可降低人肺细胞中烟曲霉、mellongalleria和秀丽隐杆线虫的感染。综上所述，我们证明了COL作为CAS增效剂对抗烟曲霉的机制是破坏细胞膜通透性和钙稳态。

本文章由计算机程序翻译，如有差异，请以英文原文为准。

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来源期刊

Nature Communications Biological Science Disciplines-

CiteScore

24.90

自引率

2.40%

发文量

6928

审稿时长

3.7 months

期刊介绍： Nature Communications, an open-access journal, publishes high-quality research spanning all areas of the natural sciences. Papers featured in the journal showcase significant advances relevant to specialists in each respective field. With a 2-year impact factor of 16.6 (2022) and a median time of 8 days from submission to the first editorial decision, Nature Communications is committed to rapid dissemination of research findings. As a multidisciplinary journal, it welcomes contributions from biological, health, physical, chemical, Earth, social, mathematical, applied, and engineering sciences, aiming to highlight important breakthroughs within each domain.