Antifungal and antibiofilm activities of chromones against nine Candida species

Abstract

Candida species are the most common cause of fungal infections, and thus the emergence of antifungal-resistant species and biofilm formation by Candida further threatens the limited availability of antifungal agents. We investigated the antifungal and antibiofilm activities of 27 chromones against nine Candida species, including Candida albicans, Candida glabrata , Candida parapsilosis , and Candida auris . Four chromone-3-carbonitriles exhibited good antifungal activity with minimum inhibitory concentrations from 5 to 50 µg/mL and significantly inhibited biofilm formation by C. albicans . Furthermore, these four chromone-3-carbonitriles markedly inhibited cell aggregation and hypha formation, which are virulence factors and prerequisites for C. albicans biofilm formation. Transcriptomic analyses showed that the most active 6-bromochromone-3-carbonitrile downregulated the expressions of hypha-forming and biofilm-related genes ( TEC1 and UME6 ) but upregulated the hyphal regulator UCF1 . Toxicity assays conducted using plant and nematode models showed that the four chromone-3-carbonitriles were non-to-mildly toxic. This study suggests that chromones bearing the 3-carbonitrile motif should be considered potential antifungal agents against Candida species. IMPORTANCE The persistence of Candida infections is due to its ability to form biofilms that enable it to resist antifungals and host immune systems. Hence, inhibitions of the biofilm formation and virulence characteristics of Candida sp. provide potential means of addressing these infections. Among various chromone derivatives tested, four chromone-3-carbonitriles showed antifungal, antibiofilm, and antivirulence activities against several Candida species. Their mode of action has been partially revealed, and their toxicity is reported here using nematode and plant models.