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 Wiederhold, Hoja P. Patterson, Thomas F Patterson, José L. Lopez-Ribot

Research output: Contribution to journalArticle

3 Citations (Scopus)

Abstract

Since its original isolation in 2009, Candida auris has spread across the globe as a causative agent of invasive candidiasis. C. auris 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 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 therapies of ebselen with clinically used antifungals. We extended our studies to different C. auris strains with various susceptibility patterns and also confirmed its antifungal activity against Candida albicans and clinical isolates of multiple other Candida 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.

Original languageEnglish (US)
Article numbere01084
JournalAntimicrobial Agents and Chemotherapy
Volume62
Issue number10
DOIs
StatePublished - Oct 1 2018

Fingerprint

Candida
Libraries
Pharmaceutical Preparations
Fungi
Invasive Candidiasis
Echinocandins
Small Molecule Libraries
Local Anti-Infective Agents
Mycoses
Fluconazole
Candidiasis
Amphotericin B
Biofilms
Candida albicans
Yeasts
ebselen
Growth
Infection
Therapeutics

Keywords

  • Antifungals
  • Candida auris
  • Candidiasis
  • Prestwick library
  • Repurposing

ASJC Scopus subject areas

  • Pharmacology
  • Pharmacology (medical)
  • Infectious Diseases

Cite this

Screening a repurposing library for inhibitors of multidrug-resistant candida auris identifies ebselen as a repositionable candidate for antifungal drug development. / Wall, Gina; Chaturvedi, Ashok K.; Wormley, Floyd L.; Wiederhold, Nathan; Patterson, Hoja P.; Patterson, Thomas F; Lopez-Ribot, José L.

In: Antimicrobial Agents and Chemotherapy, Vol. 62, No. 10, e01084, 01.10.2018.

Research output: Contribution to journalArticle

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abstract = "Since its original isolation in 2009, Candida auris has spread across the globe as a causative agent of invasive candidiasis. C. auris 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 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 therapies of ebselen with clinically used antifungals. We extended our studies to different C. auris strains with various susceptibility patterns and also confirmed its antifungal activity against Candida albicans and clinical isolates of multiple other Candida 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.",
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