Abstract
Invasive aspergillosis is one of the major causes of morbidity and mortality among invasive fungal infections. The search for new antifungal drugs becomes imperative when existing drugs are not able to efficiently treat these infections. Ebselen, is an organoselenium compound, already successfully approved in clinical trials as a repositioned drug for the treatment of bipolar disorder and prevention of noise-induced hearing loss. In this study, we aimed to reposition ebselen for the treatment of invasive aspergillosis by showing ebselen effectiveness in a murine model. For this, BALB/c mice were immunosuppressed and infected systemically with Aspergillus fumigatus. Animals were divided and treated with ebselen, voriconazole, or drug-free control, for four days. The kidneys were used for CFU count and, histopathological and cytokine analysis. Ebselen was able to significantly reduce the fungal burden in the kidneys of infected mice with efficacy comparable with voriconazole treatment as both had reductions to the same extent. The absence of hyphae and intact kidney tissue structure observed in the histopathological sections analyzed from treated groups corroborate with the downregulation of IL-6 and TNF. In summary, this study brings for the first time in vivo evidence of ebselen efficacy against invasive aspergillosis. Despite these promising results, more animal studies are warranted to evaluate the potential role of ebselen as an alternative option for the management of invasive aspergillosis in humans.
Highlights
Invasive aspergillosis (IA) remains one of the major causes of morbidity and mortality among invasive fungal infections, especially in intensive care unit patients (Ostrosky-Zeichner and Al-Obaidi, 2017)
The amount of CFUs recovered after 4 days post-infection from the kidneys of mice treated with ebselen was similar to that recovered from the kidneys of mice treated with voriconazole (p > 0.05) and significantly lower than that recovered from the kidneys of mice treated with placebo (p < 0.05) (Figure 1)
Control: mice treated with placebo; ebselen: mice treated with 10 mg.kg–1 (765.8 mmoles per mouse) of ebselen; voriconazole: mice treated with 10 mg.kg–1 (572.5 μmoles per mouse) of voriconazole
Summary
Invasive aspergillosis (IA) remains one of the major causes of morbidity and mortality among invasive fungal infections, especially in intensive care unit patients (Ostrosky-Zeichner and Al-Obaidi, 2017). The mortality in patients who received appropriate initial voriconazole therapy is up to 24% (Lestrade et al, 2019). Facing this critical scenario, in an attempt to optimize the process of searching for new drug options, repositioning drugs has become an interesting approach to speed up the discovery of new antifungal drugs. In an attempt to optimize the process of searching for new drug options, repositioning drugs has become an interesting approach to speed up the discovery of new antifungal drugs This approach decreases the conventional time of drug discovery from 10–17 to 3–12 years for repurposed compounds, as it bypasses much of the discovery and preclinical stages and phase I studies of safety (Farha and Brown, 2019)
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