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

• Published in: Antimicrobial agents and chemotherapy Vol. 62; no. 10
• Main Authors: Wall, Gina, Chaturvedi, Ashok K, Wormley, Jr, Floyd L, Wiederhold, Nathan P, Patterson, Hoja P, Patterson, Thomas F, Lopez-Ribot, José L
• Format: Journal Article
• Language: English
• Published: United States American Society for Microbiology 01-10-2018
• Subjects: Antifungal Agents; Antifungal Agents - pharmacology; Azoles; Azoles - pharmacology; Biofilms - drug effects; Candida; Candida - drug effects; Candida - metabolism; Drug Repositioning; Drug Repositioning - methods; Drug Resistance, Multiple, Fungal; Isoindoles; Organoselenium Compounds; Organoselenium Compounds - pharmacology; Susceptibility; Candida auris; Prestwick library; repurposing; antifungals; candidiasis
• ISSN: 0066-4804; 1098-6596
• DOI: 10.1128/AAC.01084-18

Since its original isolation in 2009,
has spread across the globe as a causative agent of invasive candidiasis.
is typically intrinsically resistant to fluconazole and can also be resistant to echinocandins and even amphotericin B. Thus, there is an urgent need to find new treatment options against this emerging pathogen. To address this growing problem, we 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 of those with activity against a multidrug-resistant
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
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
biofilm formation and examined the effects of combination therapies of ebselen with clinically used antifungals. We extended our studies to different
strains with various susceptibility patterns and also confirmed its antifungal activity against
and clinical isolates of multiple other
species. Furthermore, ebselen displayed a broad spectrum of antifungal actions on the basis of 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.