Abstract
Candida albicans (C. albicans) 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 C. albicans 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.
Highlights
As one of the most important human fungal pathogens, C. albicans normally resides in human body including oral cavity, gastrointestinal (GI) tracts and vagina as a non-pathogenic commensal organism (Gulati and Nobile, 2016; Prieto et al, 2016)
FTY720 exhibited a promising combinatorial effect to inhibit the growth of C. albicans when combined with Amphotericin B (AMB) (Figure 1A)
The filamentation was substantially suppressed by combinatorial treatment with both FTY720 and AMB (Figure 3A). These results indicate that combination of FTY720 and AMB exhibits a much stronger inhibitory effect on the filamentation of C. albicans than the single treatment with FTY720 or AMB
Summary
As one of the most important human fungal pathogens, C. albicans normally resides in human body including oral cavity, gastrointestinal (GI) tracts and vagina as a non-pathogenic commensal organism (Gulati and Nobile, 2016; Prieto et al, 2016). It will cause severe mucosal and even systemic candidiasis infections when the microbial homeostasis is disrupted (Achkar and Fries, 2010; Gulati and Nobile, 2016; Prieto et al, 2016). Due to its poor permeability across the membrane, an overdose of AMB must be administered to the patients in clinic, resulting in severe side effects such as nephrotoxicity
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