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Candida albicans Biofilm Chip CaBChip for High-throughput Antifungal Drug Screening
Published on: July 18, 2012
High-Throughput Screening of the Repurposing Hub Library to Identify Drugs with Novel Inhibitory Activity against
Olabayo H Ajetunmobi1, Gina Wall1, Bruna Vidal Bonifacio1
1Department of Molecular Microbiology & Immunology, South Texas Center for Emerging Infectious Diseases, The University of Texas at San Antonio, San Antonio, TX 78249, USA.
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.
Insights
Drug repurposing identified potential new antifungal therapies for candidiasis, a common hospital infection. Ebselen, temsirolimus, and BAY 11-7082 showed promise against Candida albicans and Candida auris biofilms.
Area of Science:
- Mycology
- Infectious Diseases
- Drug Discovery
Background:
- Candidiasis is a frequent nosocomial infection, with *Candida albicans* and the multi-drug-resistant *Candida auris* as primary agents.
- Both *Candida* species form biofilms, enhancing resistance and necessitating novel antifungal treatments.
- Repurposing existing drugs offers a faster route to developing new candidiasis therapies.
Purpose of the Study:
- To screen a large library of existing drugs for compounds that inhibit *Candida albicans* and *Candida auris* biofilm formation.
- To identify and validate potent anti-biofilm agents for potential therapeutic use against candidiasis.
Main Methods:
- Screening of the Broad Institute's Repurposing Hub library (>6000 compounds) for anti-biofilm activity.
- Confirmatory concentration-dependent assays to validate hits and determine anti-biofilm potency.
- In vitro antifungal spectrum testing and in vivo efficacy evaluation in murine infection models.
Main Results:
- Primary screening yielded 57 hits for *C. albicans* and 33 for *C. auris*.
- Ebselen, temsirolimus, and BAY 11-7082 were identified as leading repositionable compounds with significant anti-biofilm activity.
- These compounds demonstrated antifungal activity against various yeasts and filamentous fungi, with promising in vivo results in murine models.
Conclusions:
- Ebselen, temsirolimus, and BAY 11-7082 are promising candidates for drug repurposing against candidiasis.
- Further in vitro and in vivo research is required to confirm their therapeutic potential for candidiasis and other fungal infections.
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