The synergistic antifungal effects of sodium phenylbutyrate combined with azoles against Candida albicans via the regulation of the Ras–cAMP–PKA signalling pathway and virulence

Abstract

The pathogenic fungus Candida albicans is one of the most commonly clinically isolated fungal species, and its resistance to the antifungal drug fluconazole is known to be increasing. In this paper, we sought to characterize the effect of sodium phenylbutyrate used alone or in combination with azoles against resistant C. albicans. The minimum inhibitory concentrations and sessile minimum inhibitory concentrations were determined to explore the synergistic mechanism. The results showed that sodium phenylbutyrate exerted clear antifungal activity and that the combination of sodium phenylbutyrate and azoles functioned synergistically to combat resistant C. albicans. In our study of the mechanism, we initially found that the combination therapy resulted in the inhibition of hypha growth, the increased penetration of fluconazole through C. albicans biofilm, and the decreased expression of hyphae-related genes and the upstream regulatory genes (CYR1 and TPK2) of the Ras–cAMP–PKA signalling pathway, as determined by RT–PCR. In addition, the combination treatment decreased the extracellular phospholipase activities and the expression of aspartyl proteinase genes (SAP1–SAP3). The synergistic antifungal effects of the combination of sodium phenylbutyrate and azoles against resistant C. albicans was mainly based on the regulation of the Ras–cAMP–PKA signalling pathway, hyphae-related genes, and virulence factors.