Novel Small Molecule for Treatment of Oral and Systemic Candidiasis

Objective: Candida albicans (Ca) is the major fungal pathogen in humans which causes both superficial mucosal and systemic mycoses. Emergence of drug resistant Ca in the past decade highlights the dire need of novel antifungal agents. In the present study, we characterized antifungal activity of a novel small molecule using oral and systemic candidiasis models. Methods: A library of 50,000 small molecules was systematically screened for antifungal activity. Small molecule (SM21) with most potent activity was further characterized. First, cytotoxicity of SM21 was evaluated by Vero cells and human oral keratinocytes (HOK) using MTT assays in vitro and in vivo mouse model. Second, ability of SM21 to inhibit yeast-to-hypha transition of Ca under strong inducing conditions was examined. Third, anti-biofilm activity of SM21 was investigated using standard methodology. Candida-HOK co-culture model was used to evaluate efficacy of SM21 in vitro. In vivo antifungal activity was tested by oral candidiasis and systemic candidiasis mouse models. Lastly, the mechanism of antifungal activity was explored by transcriptomic and proteomic approaches. Results: Cytotoxicity of SM21 was minimal and proved to be safe both in vitro and in vivo. SM21 was a potent inhibitor of yeast-to-hypha transition and biofilm formation of Ca. Interestingly, SM21 was able to prevent both oral and systemic candidiasis in mice models, possibly through MAPK/PKA pathways as suggested by mechanistic studies. Conclusion: We have discovered a novel small molecule with strong antifungal activity which could be used to treat both oral and systemic mycoses. (HKU Seed funding for CJS & LPS)