High Throughput Screening of Repurposing Libraries in Search for Drugs with Novel Inhibitory Activity Against Candida albicans and Candida auris Biofilm Formation

Candida albicans remains the most common causative agent of candidiasis, but infections caused by non-albicans Candida species have become increasingly common. Candida auris, a multidrug-resistant fungal pathogen, is now classified as an urgent threat to public health by the U.S Centers for Disease Control and Prevention, and the Global Antimicrobial Resistance Surveillance System (GLASS) of WHO has highlighted the need for global surveillance schemes to identify and monitor antifungal resistance in Candida. Biofilms formed by these organisms are typically challenging to treat as they have been reported to be resistant to currently available antifungal drugs. Therefore, it is essential to identify novel drugs with antifungal activity to adequately control and treat these infections. Here we have used a drug repurposing approach to tackle this problem. In this project, we have screened several repurposing libraries to identify drugs with novel anti-biofilm activity against C. albicans and C. auris. A screen of the Pandemic Response Box identified everolimus, MMV1633966 and MMV1593537 as active against C. albicans and C. auris biofilm formation. After developing a new 384-well plate-based model of Candida biofilm formation that allows for true high throughput screening, we screened the Calibr ReFRAME and Repurposing Hub libraries. We confirmed 101 hit compounds against C. albicans from the ReFRAME library and we further characterized three leading repositionable candidates tazomeline, AXT-914, and CI 201. We identified 25 repositionable candidates active against C.albicans from the Repurposing Hub with BAY 11-7082 and temsirolimus being the leading repositionable candidates. Our results confirm the validity of a repurposing approach, where the leading compounds could be repositioned as antifungals to combat the threat of Candida biofilms, and potentially other fungal infections.