ena-STUDY-FRAUNHOFER IGB-01-04-2019-13:09:03:256-276
Stable Redox-Cycling Nitroxide Tempol has Antifungal and Immune-modulatory Properties
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 culture-based 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 stress responses against azoles, 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 release of pro-inflammatory cytokines, such as interleukin 8. In a systemic mouse model tempol was partially protective with a significant reduction of fungal burden in kidneys of infected animals during infection onset.  The results obtained proposed tempol as a promising new antifungal compound and opens new opportunities for the future development of novel therapies.
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 culture-based 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 stress responses against azoles, 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 release of pro-inflammatory cytokines, such as interleukin 8. In a systemic mouse model tempol was partially protective with a significant reduction of fungal burden in kidneys of infected animals during infection onset.  The results obtained proposed tempol as a promising new antifungal compound and opens new opportunities for the future development of novel therapies.