AUTHOR=Su Liu-Yan , Ni Guang-Hui , Liao Yi-Chuan , Su Liu-Qing , Li Jun , Li Jia-Sheng , Rao Gao-Xiong , Wang Rui-Rui 

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

JOURNAL=Frontiers in Microbiology

VOLUME=12

YEAR=2021

URL=https://www.frontiersin.org/journals/microbiology/articles/10.3389/fmicb.2021.692693

DOI=10.3389/fmicb.2021.692693

ISSN=1664-302X

ABSTRACT=<p>The increased resistance of <italic>Candida albicans</italic> 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 <italic>C. albicans</italic> resistance, has gained traction. This study assessed the effect of 6,7,4′-O-triacetylscutellarein (TA) combined with fluconazole (FLC) on <italic>C. albicans in vitro</italic> and <italic>in vivo</italic>. TA combined with FLC showed good synergistic antifungal activity against drug-resistant <italic>C. albicans in vitro</italic>, 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 <italic>C. albicans</italic>. The combined antifungal efficacy of TA and FLC was evaluated <italic>in vivo</italic> in a mouse systemic fungal infection model. TA combined with FLC prolonged the survival rate of mice infected with drug-resistant <italic>C. albicans</italic> and reduced tissue invasion. TA combined with FLC also significantly inhibited the yeast-hypha conversion of <italic>C. albicans</italic> 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 <italic>C. albicans</italic>. Therefore, this study provides a basis for the treatment of drug-resistant <italic>C. albicans</italic> infections.</p>