Ojectives: Fungal infections represent an increasing threat to an expanding population of at risk patients; but the impact of these diseases on human health is not widely appreciated. The mortality associated with some of these infections remain unacceptably high. Because fungi are eukaryotic, there is a paucity of selective targets that can be exploited for antifungal drug development. As a result, the current antifungal armamentarium is very limited. Furthermore, the antifungal drug pipeline is mostly dry. There is no doubt that novel antifungals and new approaches to develop them are urgently warranted. Unlike the costly and time consuming process of de novo drug discovery, drug repurposing is a novel method to reduce the time, cost and risk associated with drug innovation. Methods: The present studies build upon the recent discovery by our group of the potent antifungal activity of FDA-approved drug Auranofin, which we originally identified in high content screenings of the Prestwick library against Candida albicans biofilms. MICs were determined in accordance with the CLSI M27-A3 (for yeast) and M38-A2 (for filamentous fungi) reference standards for antifungal susceptibility testing. We also performed in-vivo evaluation of these drugs in the murine models of systemic cryptococcosis and hematogenously disseminated candidiasis Results: Screening the same library against other pathogenic fungi resulted in the identification of Ebselen as a leading compound displaying potent antifungal activity against different fungi. We observed increased survival of mice in groups treated with Auranofin and Ebselen compared to mock treated groups. Both drugs are organometallics and have many advantageous qualities including oral bioavailability, potent microbicidal activity in a clinical range and very low frequency of resistance Conclusion: In conclusion, repositioning old drugs can significantly decrease the time and effort that it takes to develop novel antifungal therapeutics, which represents a pressing and unmet clinical need due to the devastating nature of fungal infections. Thus, the present study seeks to provide further valuable evidence that both drugs have significant promise to be repositioned as novel antifungals for the treatment of fungal infections.

6 / Repurposing FDA-approved Ebselen and Auranofin as anti-fungal drugs: teaching old drugs new tricks