Repurposing of auranofin and honokiol as antifungals against species and the related fungus .

The slowing-down drug-discovery emphasized the importance of repurposing old drugs. This is particularly true when combating infections caused by therapy-refractory microorganisms, such as species and . Recent studies on responses to oxidative stress underscored the importance of targeting the underlying mechanisms. Auranofin, ebselen, PX-12, honokiol, and to a lesser extent, conoidin A are known to disturb redox-homeostasis systems in many organisms. Their antifungal activity was assessed against 27 isolates belonging to the major species: , and . Auranofin and honokiol were the most active against all species (mean MIC values of 2.875 and 6.143 μg/ml, respectively) and against isolates (mean MIC values of 4.0 and 3.563μg/ml respectively). Combinations of auranofin with voriconazole or honokiol revealed additive effects against 9/27 and 18/27 isolates, respectively. Synergistic interaction between auranofin and honokiol was only found against one isolate of . The effects of auranofin upon exposure to oxidative stress were also investigated. For all species except , the maximal growth in the presence of auranofin significantly decreased when adding a sublethal dose of menadione. The analysis of the expression of genes encoding oxidoreductase enzymes upon exposure of to honokiol unveiled the upregulation of many genes, especially those coding peroxiredoxins, thioredoxin reductases, and glutaredoxins. Altogether, these data suggest that auranofin and honokiol act via dampening the redox balance and support their repurposing as antifungals against species and .