Repurposing for Antifungal Drug Development: Large-scale Screening of the Library of Pharmacologically Active Compounds (LOPAC®1280) for Identification of Candida Albicans Biofilm Inhibitors
Fungal infections represent an increasing threat to an expanding population of immune- and medically-compromised patients. Candida albicans is the major human fungal pathogen that causes candidiasis, now the third most common nosocomial infection in US hospitals with high mortality rates. The existing arsenal of antifungal drugs is very limited and better therapeutic strategies are urgently needed, particularly for the treatment of biofilm associated infections which are intrinsically resistant to most clinically-used antifungal agents.
We have screened the Library of Pharmacologically Active Compounds (LOPAC®1280), which includes 1,280 FDA-approved drugs and other pharmaceutically relevant structures, in search for inhibitors of C. albicans biofilm formation. Importantly, drug-like molecules in this library impact most signaling pathways and cover all major known drug targets. Using a 96-well micro titer plate-based large-scale screening assay developed in our laboratory, our initial screen identified 37 pharmacologically active agents that inhibit C. albicans biofilm formation. Secondary experiments included dose-response assays to confirm the activity and determine the potency of initial hits and evaluating the activity of confirmed compounds against preformed biofilms. Since the process of developing a brand-new medication is long (about 15 years) and expensive (over 1 billion dollars), this strategy of repurposing or repositioning already existing drugs opens a new, rapid and cost-effective avenue for antifungal drug development. This project has identified 3 leading candidates that show promising activity against biofilm formation.