Abstract
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.
Highlights
In recent years, the morbidity and mortality of invasive fungal infections have remained high, especially in patients with weakened immunity and hospitalized patients with severe illness (Noble et al, 2016)
We studied the antifungal activity of TA and SL and unexpectedly found that TA combined with FLC has good antifungal activity against C. albicans, especially the resistant strains
TA combined with FLC showed an indifference effect and a strong synergistic effect on sensitive and resistant strains (FICI, 2.27 and 0.18, respectively)
Summary
The morbidity and mortality of invasive fungal infections have remained high, especially in patients with weakened immunity and hospitalized patients with severe illness (Noble et al, 2016). Combined Antifungal Activity of 6,7,4 -O-Triacetylscutellarein life-threatening invasive infections (Rajasekharan et al, 2018). Long-term, high-dose use of fluconazole can lead to the emergence of drug-resistant strains, which poses a major challenge to the clinical prevention and treatment of C. albicans infection (Zhang et al, 2020). It is necessary to find new antifungal drugs or effective treatment strategies for inhibiting fungal resistance. Studies have shown that using natural compounds derived from traditional Chinese medicine and their derivatives combined with fluconazole has an excellent synergistic effect against drug-resistant C. albicans (Gong et al, 2019). We studied the antifungal activity of TA and SL and unexpectedly found that TA combined with FLC has good antifungal activity against C. albicans, especially the resistant strains
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