Salvianolic acid B synergizes with azoles against Candida glabrata cells in vulvovaginal candidiasis

Introduction The rising prevalence of antifungal resistance poses a significant threat to global health, with Candida glabrata ( C. glabrata ) emerging as a particular concern due to its increasing incidence in clinical settings and the intrinsic low susceptibility to azoles. Salvianolic acid B (SAB), a major bioactive component extracted from Salvia miltiorrhiza , exhibits potent antioxidant properties; however, its potential as an antifungal remains unexplored. Objectives This study aimed to evaluate the antifungal efficacy of SAB alone and in combination with azoles against C. glabrata , both in vitro and in vivo , and to elucidate the underlying mechanisms. Methods The antifungal efficacy of SAB alone and in combination with fluconazole (FLC), itraconazole (ITC), and voriconazole (VRC) was assessed against C. glabrata . Synergistic interactions were determined via checkerboard microdilution assays and time-kill studies. The cytotoxicity of SAB was evaluated using lactate dehydrogenase (LDH) release assays, while in vivo efficacy was examined using a Galleria mellonella ( G. mellonella ) infection model. Additionally, mechanistic insights were obtained through scanning and transmission electron microscopy (SEM/TEM) to visualize morphological and ultrastructural alterations. Results SAB exhibited marked synergistic activity with azoles against azole-resistant C. glabrata isolates. Importantly, SAB demonstrated negligible cytotoxicity toward mammalian cells. In the G. mellonella infection model, combination therapy with FLC and SAB significantly improved larval survival compared to FLC alone. SEM and TEM revealed extensive membrane disruption, cytoplasmic dissolution, and subcellular damage in SAB and FLC treated cells, consistent with the observed synergistic antifungal activity. Conclusion SAB synergistically enhances azoles activity against drug-resistant C. glabrata both in vitro and in vivo , with mechanisms involving membrane disruption and ultrastructural damage. These findings position SAB as a promising natural adjuvant for combination therapy against drug-resistant Candida infections.