High content screening for the identification of novel antifungal agents targeting Candida albicans biofilm formation and filamentation
Fungal infections represent an increasing health threat to immunocompromised patients and Candida albicans is the major human fungal pathogen associated with unacceptably high mortality rates. The existing arsenal of antifungal drugs is very limited and better treatment strategies are urgently needed. Targeting functions essential for infection, such as virulence factors, represents an attractive, yet clinically unexploited alternative for the development of antifungal agents. We have used high content screening techniques to identify small molecule compounds from Chembridge's NOVACoreTM and DIVERSetTM chemical libraries, as well as compounds present in a repository from the National Cancer Institute, with inhibitory activity on C. albicans filamentation and biofilm formation, two major virulence factors contributing to the pathogenesis of candidiasis. Based on their potency, lack of toxicity and presumed pharmacokinetic properties, four of these compounds represent promising leads for the development of new antifungal agents and were tested in vivo in the murine model of hematogenously disseminated candidiasis. Evaluation of protective effects was performed by survival, determination of fungal organ burden and histology. Results indicated that treatment with each compound significantly increased survival compared to the control group. Unlike treatment with conventional antifungal agents, the protective effects were not associated with inhibition of growth, but rather with an effect on fungal morphology, as the compounds inhibited morphogenetic conversions in vivo, resulting in decreased virulence and associated pathology. Thus, these compounds represent advanced candidates for the development of novel antifungal agents with new molecular structures, as well as, new targets and mechanism(-s) of action.