Screening a Repurposing Library for Inhibitors of Multidrug-Resistant Candida auris Identifies Ebselen as a Repositionable Candidate for Antifungal Drug Development

Gina Wall, Ashok K. Chaturvedi, Floyd L. Wormley, Nathan P. Wiederhold, Hoja P. Patterson, Thomas F. Patterson, José L. Lopez-Ribot

Since its original isolation in 2009, Candida auris has spread across the globe as a causative agent of invasive candidiasis. C. auris is usually intrinsically resistant to fluconazole and can also be resistant to echinocandins and even amphotericin B. Thus, finding new treatment options against this emerging pathogen is urgent. To address this growing problem, we have performed a screen of the Prestwick Chemical Library, a repurposing library of 1,280 small molecules, consisting mostly of approved off-patent drugs, in search for those with activity against a multidrug resistant C. auris isolate. Our initial screen, using standardized susceptibility testing methodologies, identified nine miscellaneous compounds with no previous clinical indication as antifungals or antiseptics that displayed activity against C. auris Confirmation and follow-up studies identified ebselen as the drug displaying the most potent activity, with 100% inhibition of growth detected at concentrations as low as 2.5 μM. We further evaluated the ability of ebselen to inhibit C. auris biofilm formation and examined the effects of combination therapy of ebselen with clinically used antifungals. We extended our studies to different C. auris strains with varying susceptibility patterns and also confirmed its antifungal activity against C. albicans and clinical isolates of multiple other Candida species. Furthermore, ebselen displays broad antifungal spectrum of action based on its activity against a variety of medically important fungi, including yeasts and molds. Overall our results indicate the promise of ebselen as a repositionable agent for the treatment of candidiasis and possibly other mycoses, and in particular for the treatment of infections refractory to conventional treatment with current antifungals.