Fingolimod Potentiates the Antifungal Activity of Amphotericin B

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.

Immunomodulatory drug fingolimod (FTY720) restricts the growth of opportunistic yeast Candida albicans in vitro and in a mouse candidiasis model

“…In line with our study, a recent ex vivo study by Wei and colleagues pointed to the fungicidal effect of FTY720, which synergized the effect of amphotericin B [39]. Wei et al showed that this fungicidal effect is present against non-albicans Candida spp., Saccharomyces cerevisiae, and Cryptococcus neoformans as well as C. albicans [39]. They also showed that 0.011 mg/ mL of FTY720 affects C. albicans' growth rate similar to 0.08 mg/L of amphotericin B [39].…”

“…Wei et al showed that this fungicidal effect is present against non-albicans Candida spp ., Saccharomyces cerevisiae , and Cryptococcus neoformans as well as C . albicans [ 39 ]. They also showed that 0.011 mg/mL of FTY720 affects C .…”

“…They also showed that 0.011 mg/mL of FTY720 affects C . albicans’ growth rate similar to 0.08 mg/L of amphotericin B [ 39 ]. In an attempt to characterize the mechanism of this effect, they demonstrated that FTY720 induces production and hyperaccumulation of reactive oxygen species (ROS) in a dose-dependent manner.…”

“…In an attempt to characterize the mechanism of this effect, they demonstrated that FTY720 induces production and hyperaccumulation of reactive oxygen species (ROS) in a dose-dependent manner. Scavenging the ROS from the samples using N-acetyl cysteine compromised the fungicidal effect of FTY720 significantly, therefore, Wei et al suggested hyperaccumulation of ROS as the mechanism of FTY720’s fungicidal effect [ 39 ]. ROS accumulation in fungi induced by unphosphorylated FTY720 has been observed in previous studies as well [ 15 , 40 ], the upstream processes of which are areas of active investigation.…”

“…The innate immunity is absent in vitro , therefore, higher concentrations of FTY720 are needed to raise the ROS levels up to the threshold intolerable by the yeast. The ROS generation induced by FTY720 in vivo , although may not be adequate by itself, is added by the ROS produced by the innate immune cells, attracts more cells to the frontline [ 43 ], facilitates phagocytizing, and eases the killing of fungi by the phagocytes [ 39 ]. Nevertheless, countless processes are involved in fungal proliferation and expansion in vivo ; determination of our observations’ mechanistic background could be an interesting subject for future studies.…”