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The increased resistance of Candida albicans to conventional antifungal drugs poses a huge challenge to the clinical treatment of this infection. In recent years, combination therapy, a potential treatment method to overcome C. albicans resistance, has gained traction. This study assessed the effect of 6,7,4′-O-triacetylscutellarein (TA) combined with fluconazole (FLC) on C. albicans in vitro and in vivo. TA combined with FLC showed good synergistic antifungal activity against drug-resistant C. albicans in vitro, with a partial inhibitory concentration index (FICI) of 0.0188–0.1800. In addition, the time-kill curve confirmed the synergistic effect of TA and FLC. TA combined with FLC showed a strong synergistic inhibitory effect on the biofilm formation of resistant C. albicans. The combined antifungal efficacy of TA and FLC was evaluated in vivo in a mouse systemic fungal infection model. TA combined with FLC prolonged the survival rate of mice infected with drug-resistant C. albicans and reduced tissue invasion. TA combined with FLC also significantly inhibited the yeast-hypha conversion of C. albicans and significantly reduced the expression of RAS-cAMP-PKA signaling pathway-related genes (RAS1 and EFG1) and hyphal-related genes (HWP1 and ECE1). Furthermore, the mycelium growth on TA combined with the FLC group recovered after adding exogenous db-cAMP. Collectively, these results show that TA combined with FLC inhibits the formation of hyphae and biofilms through the RAS-cAMP-PKA signaling pathway, resulting in reduced infectivity and resistance of C. albicans. Therefore, this study provides a basis for the treatment of drug-resistant C. albicans infections.

Candida albicans is a ubiquitous clinical fungal pathogen. Prolonged use of the first-line antifungal agent fluconazole (FLC) has intensified fungal resistance and limited its effectiveness for the treatment of fungal infections. The combined administration of drugs has been extensively studied and applied. SWL-1 is a lignin compound derived from the Traditional Chinese Medicine Schisandra chinensis. In this study, we show that SWL-1 reverses resistance to fluconazole in C. albicans when delivered in combination, with a sharp decrease in the IC50 of fluconazole from >200 to 3.74 ± 0.25 μg/ml, and also reverses the fluconazole resistance of C. albicans in vitro, with IC50 from >200 to 5.3 ± 0.3 μg/ml. Moreover, killing kinetics curves confirmed the synergistic effects of fluconazole and SWL-1. Intriguingly, when SWL-1 was administered in combination with fluconazole in a mouse model of systemic infection, the mortality of mice was markedly decreased and fungal colonization of the kidney and lung was reduced. Further mechanistic studies showed that SWL-1 significantly decreased intracellular adenosine 5’-triphosphate (ATP) levels and inhibited the function of the efflux pump responsible for fluconazole resistance of C. albicans. Proteomic analysis of the effects of SWL-1 on C. albicans showed that several enzymes were downregulated in the glycolytic pathway. We speculate that SWL-1 significantly decreased intracellular ATP levels by hindering the glycolysis, and the function of the efflux pump responsible for fluconazole resistance of C. albicans was inhibited, resulting in restoration of fluconazole sensitivity in FLC-resistant C. albicans. This study clarified the effects and mechanism of SWL-1 on C. albicans in vitro and in vivo, providing a novel approach to overcoming fungal resistance.