Abstract
Invasive mycoses remain underdiagnosed and difficult to treat. Hospitalized individuals with compromised immunity increase in number and constitute the main risk group for severe fungal infections. Current antifungal therapy is hampered by slow and insensitive diagnostics and frequent toxic side effects of standard antifungal drugs. Identification of new antifungal compounds with high efficacy and low toxicity is therefore urgently required. We investigated the antifungal activity of tempol, a cell-permeable nitroxide. To narrow down possible mode of action we used RNA-seq technology and metabolomics to probe for pathways specifically disrupted in the human fungal pathogen Candida albicans due to tempol administration. We found genes upregulated which are involved in iron homeostasis, mitochondrial stress, steroid synthesis, and amino acid metabolism. In an ex vivo whole blood infection, tempol treatment reduced C. albicans colony forming units and at the same time increased the release of pro-inflammatory cytokines, such as interleukin 8 (IL-8, monocyte chemoattractant protein-1, and macrophage migration inhibitory factor). In a systemic mouse model, tempol was partially protective with a significant reduction of fungal burden in the kidneys of infected animals during infection onset. The results obtained propose tempol as a promising new antifungal compound and open new opportunities for the future development of novel therapies.
Highlights
In recent decades, susceptibility to infection due to reduced host immunity is the most common driving force for the rise of incidences of severe fungal infections
We explored the antifungal activity of tempol against C. albicans investigated pathways engaged in the treated fungal cells in order to narrow down a possible mode of action and tested the compound in a systemic candidiasis model
Since interference with antioxidant pathways in fungal pathogens was suggested as therapy option (Leal et al, 2012) we wanted to investigate whether radical scavenger tempol (Figure 1A) could hamper C. albicans growth
Summary
Susceptibility to infection due to reduced host immunity is the most common driving force for the rise of incidences of severe fungal infections. Fungemia has an annual prevalence of 300,000 cases with a mortality rate of 30–50% (Zilberberg et al, 2008; Arendrup, 2010) and emerging multi-resistant strains, such as of Candida auris responsible for several nosocomial outbreaks in recent years, increase clinical concern (Quindos et al, 2018). A common trend of the past years has been that pharmaceutical companies withdrew from development of new antimicrobial agents due to reservations concerning the market share, manifold risks during development as well as cost and time effort through clinical phases (Spellberg et al, 2004; Edwards et al, 2018). The rising incidences of severe mycoses, emergence of resistant strains, and the adverse side effects of current antifungal therapies illustrate the urgent need for new options
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