Combined Antifungal Effect of Plant Extracts and Itraconazole Against Candida albicans

Combination therapy has emerged as an alternative to improve the efficacy of currently used antifungal therapy, as it can achieve a better therapeutic effect (synergism), minimize undesirable effects compared to the use of each component independently, and delay the evolution of resistance. The aim of this study was to increase the sensitivity of Candida albicans to itraconazole by combined treatment with plant extracts, using experimental design methodologies (mixture design). Synergy studies of binary mixtures were carried out using the checkerboard method, while synergy studies of ternary mixtures were performed by applying the simplex-centroid mixture design method. The chemical composition of the extracts under study was explored by ultra-high performance liquid chromatography. Thirteen extracts that synergized itraconazole activity were identified using the checkerboard method. The simplex-centroid design approach allowed predicting ternary mixtures (composed of two extracts and itraconazole) with optimized activity, proving to be a useful tool for estimating antifungal interactions between components of complex mixtures. Ternary mixtures containing Scoparia dulcis , Ameghinoa patagonica , and Gaillardia megapotamica extracts in combination with Zuccagnia punctata extract and itraconazole simultaneously showed optimized activity with minimal concentration of the antifungal. The synergistic effect shown by these combinations may contribute to their successful application in alternative therapies against the pathogenic fungus C. albicans. Graphical Abstract