Abstract
The human fungal pathogen Candida albicans can form biofilms on biotic and abiotic surfaces, which are inherently resistant to antifungal drugs. We screened the Chembridge Small Molecule Diversity library containing 30,000 “drug-like” small molecules and identified 45 compounds that inhibited biofilm formation. These 45 compounds were then tested for their abilities to disrupt mature biofilms and for combinatorial interactions with fluconazole, amphotericin B, and caspofungin, the three antifungal drugs most commonly prescribed to treat Candida infections. In the end, we identified one compound that moderately disrupted biofilm formation on its own and four compounds that moderately inhibited biofilm formation and/or moderately disrupted mature biofilms only in combination with either caspofungin or fluconazole. No combinatorial interactions were observed between the compounds and amphotericin B. As members of a diversity library, the identified compounds contain “drug-like” chemical backbones, thus even seemingly “weak hits” could represent promising chemical starting points for the development and the optimization of new classes of therapeutics designed to target Candida biofilms.
Highlights
Candida albicans is a normal commensal of the human microbiota that asymptomatically colonizes the skin, the mouth, and the gastrointestinal tract of healthy humans [1,2,3,4].C. albicans is one of the most common fungal pathogens of humans, typically causing superficial mucosal infections in healthy individuals [1,5,6,7,8,9,10,11]
The Chembridge Small Molecule Diversity library of 30,000 “drug-like” compounds covering a wide range of chemical scaffolds, diverse chemical backbones, chemotypes, and pharmacophores was robotically screened for compounds that inhibit C. albicans biofilm formation
(Figure 1a), where the compound of interest was added during the 90 min initial step of biofilm formation and washed out
Summary
Candida albicans is a normal commensal of the human microbiota that asymptomatically colonizes the skin, the mouth, and the gastrointestinal tract of healthy humans [1,2,3,4].C. albicans is one of the most common fungal pathogens of humans, typically causing superficial mucosal infections in healthy individuals [1,5,6,7,8,9,10,11]. A notable virulence trait of C. albicans is its ability to form biofilms, multilayered, structured communities of cells that can grow on biotic and abiotic surfaces, such as mucosal surfaces and implanted medical devices (e.g., catheters, dentures, and heart valves) [1,2,10,16,17,18,19,20,21] These biofilms are often resistant to antifungal drugs at concentrations that are normally effective against planktonic (free-floating) cells [20,21,22,23,24,25]. Since there are no biofilm-specific therapeutics available on the market today and only three major classes of antifungal drugs used to treat fungal infections in humans, the development of new therapeutics effective against C. albicans biofilms is an important and unmet medical need
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