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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.

Antifungal Activity and Potential Mechanism of 6,7, 4′-O-Triacetylscutellarein Combined With Fluconazole Against Drug-Resistant C. albicans