State Key Laboratory of Oncogenes and Related Genes, Center for Single-Cell Omics, School of Public Health, Shanghai Jiao Tong University School of Medicine, Shanghai, China.
Department of Laboratory Medicine, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China.
Front Cell Infect Microbiol. 2021 Apr 23;11:627917. doi: 10.3389/fcimb.2021.627917. eCollection 2021.
() is an opportunistic human fungal pathogen that can cause severe infection in clinic. Its incidence and mortality rate has been increasing rapidly. Amphotericin B (AMB), the clinical golden standard antifungal agent, has severe side effects that limit its clinical application. Thus, lowering the concentration and increasing the efficacy of AMB in a combinatorial antifungal therapy have been pursued by both industry and academia. Here we identify that fingolimod (FTY720), an immunomodulatory drug used for oral treatment of relapsing-remitting multiple sclerosis, can potentiate the efficacy of AMB against growth synergistically. Furthermore, we observe an antifungal efficacy of FTY720 in combination with AMB against diverse fungal pathogens. Intriguingly, cells treated with both drugs are hypersensitive to endothelial endocytosis and macrophage killing. This is later found to be due to the hyperaccumulation of reactive oxygen species and the corresponding increase in activities of superoxide dismutase and catalase in the cells that received combinatorial treatment. Therefore, the combination of AMB and FTY720 provides a promising antifungal strategy.
() 是一种机会性人类致病真菌，可在临床上引起严重感染。其发病率和死亡率呈快速上升趋势。两性霉素 B (AMB)，作为临床金标准抗真菌药物，具有严重的副作用，限制了其临床应用。因此，工业界和学术界都在追求降低 AMB 浓度并提高其在联合抗真菌治疗中的疗效。在这里，我们发现用于口服治疗复发性多发性硬化症的免疫调节药物芬戈莫德 (FTY720) 可以协同增强 AMB 对 的生长的疗效。此外，我们观察到 FTY720 与 AMB 联合使用对多种真菌病原体具有抗真菌功效。有趣的是，用两种药物处理的细胞对内皮细胞胞吞作用和巨噬细胞杀伤作用敏感。后来发现，这是由于细胞中活性氧的过度积累以及接受联合治疗的细胞中超氧化物歧化酶和过氧化氢酶的活性相应增加所致。因此，AMB 和 FTY720 的联合使用为抗真菌策略提供了一个有前景的选择。
