High-Throughput Screening of the Repurposing Hub Library to Identify Drugs with Novel Inhibitory Activity against Candida albicans and Candida auris Biofilms

Abstract

Candidiasis is one of the most frequent nosocomial infections affecting an increasing number of at-risk patients. Candida albicans remains the most frequent causative agent of candidiasis, but, in the last decade, C. auris has emerged as a formidable multi-drug-resistant pathogen. Both species are fully capable of forming biofilms, which contribute to resistance, increasing the urgency for new effective antifungal therapies. Repurposing existing drugs could significantly accelerate the development of novel therapies against candidiasis. Here, we have screened the Repurposing Hub library from the Broad Institute, containing over 6000 compounds, in search for inhibitors of C. albicans and C. auris biofilm formation. The primary screen identified 57 initial hits against C. albicans and 33 against C. auris. Confirmatory concentration-dependent assays were used to validate the activity of the initial hits and, at the same time, establish their anti-biofilm potency. Based on these results, ebselen, temsirolimus, and compound BAY 11-7082 emerged as the leading repositionable compounds. Subsequent experiments established their spectrum of antifungal activity against yeasts and filamentous fungi. In addition, their in vivo activity was examined in the murine models of hematogenously disseminated C. albicans and C. auris infections. Although promising, further in vitro and in vivo studies are needed to confirm their potential use for the therapy of candidiasis and possibly other fungal infections.

Keywords: Candida spp.; antifungal; biofilm; repurposing; screening.

Figure 1

Graphical representation of results from the initial screens for inhibitors of biofilm formation against C. albicans (A) and C. auris (B). The dotted lines indicate the 70% arbitrary threshold for initial hit identification.

Figure 2

Evaluation of protective effects of treatment with ebselen (A), temsirolimus (B), and compound BAY 11-7082 (C) in the murine model of hematogenously disseminated infection by C. albicans.

Figure 3

Evaluation of protective effects of treatment with ebselen (A) and temsirolimus (B) in the murine model of hematogenously disseminated infection by C. auris.