Carnero Laura Garcia, Li Xingyue, de Castro Patrícia Alves, Pinzan Camila Figueiredo, Campanella Jonatas Erick Maimoni, Malavazi Iran, Yoshimura Mami, Isuhuaylas Luis Alberto Vega, Yashiroda Yoko, Boone Charles, Osherov Nir, Fallah Sara, Davie Taylor, Robbins Nicole, Cowen Leah, Lu Ling, Dos Reis Thaila Fernanda, Goldman Gustavo H
Faculdade de Ciências Farmacêuticas de Ribeirão Preto, Universidade de São Paulo, Ribeirão Preto, Brazil.
Department of Clinical Laboratory, Nanjing Drum Tower Hospital, College of Life Science, Nanjing Normal University, Nanjing, Jiangsu, China.
Nat Commun. 2025 Jul 1;16(1):5967. doi: 10.1038/s41467-025-60991-z.
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.
真菌感染每年导致超过250万人死亡。由于新出现的抗真菌药物耐药性，迫切需要新的策略来对抗危及生命的真菌疾病。在此，通过筛选来自三个化学文库的5297种化合物，我们证明抗菌剂多粘菌素（COL）可以增强抑菌棘白菌素类药物卡泊芬净（CAS）和阿尼芬净，以及结构不同的靶向细胞壁的抗真菌药物ibrexafungerp对烟曲霉的作用。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对于应对钙限制条件至关重要，添加钙可挽救对COL的敏感性。COL + CAS可降低人肺细胞、大蜡螟和秀丽隐杆线虫中的烟曲霉感染。总之，我们证明COL作为CAS对烟曲霉增效剂的机制是破坏细胞膜通透性和钙稳态。
