Discovery of new antifungal for denture stomatitis and oral candidiasis

Abstract

OBJECTIVES: Candida is a major fungal pathogen of humans. Oral candidiasis is unacceptably prevalent among immuno-compromised host populations and denture wearers. Treatment for oral candidiasis and denture stomatitis is challenging due to emergence of drug resistant yeast strains, and the limited number of available antifungals. Therefore, there is an urgent need to develop more efficient novel antifungal agents. Recently, we uncovered a novel antifungal small molecule SM21 after screening a small-molecule library of 50,000 units. In this study, we comprehensively investigated the efficacy and mechanism of SM21 for denture stomatitis and oral candidiasis. METHODS: In vitro efficacy of SM21 was evaluated using biofilm model of clinical denture stomatitis Candida isolates on denture acrylic, by XTT reduction assay, Confocal and Scanning electron microcopy. Next, in vivo efficacy of SM21 was evaluated in oral candidiasis murine model. Structure-activity relationship was investigated by screening a series of functional analogues of SM21 for their antifungal activities. State-of-art techniques, proteomics and transcriptomics, were used to investigate the mechanism of action. RESULTS: SM21 showed promising antifungal properties against Candida denture stomatitis in vitro biofilm model, and in vivo oral candidiasis models. Minimum inhibitory concentration (MIC) of SM21 was shown to be comparable to existing antifungal agents. SM21 was effective against oral Candida infections and did not show any detrimental effects in vivo. One functional analogue was revealed to possess comparable antifungal properties as SM21 and the structure-activity relationship was established. Proteomics and transcriptomics analysis showed SM21 may act on hyphal specific proteins at sub-MIC and protein targets in Candida cells at MIC. CONCLUSIONS: This newly discovered antifungal agent appears to be effective and efficient both in vitro and in vivo for the management of oral candidiasis and denture stomatitis. It has enormous therapeutic potential, in particular, for recalcitrant Candida infections.