Identification of Ermiao Fang Jiawei extract as potential synergist against fluconazole-resistant <i>Candida albicans in vitro</i> and in a vulvovaginal candidiasis model

Drug resistance often limits the efficacy of Fluconazole (FCZ) against vulvovaginal candidiasis (VVC). Ermiao Fang Jiawei (EMFJ) is composed of <i>Atractylodis rhizoma</i>, <i>Phellodendri chinensis</i> cortex, <i>Cnidii fructus</i>, and Charred <i>Sanguisorbae radix</i>. UHPLC-MS/MS elucidated atractylodin, berberine, osthole, gallic acid, and ellagic acid as the main components of ethanolic extract of EMFJ (Eth-EMFJ). Eth-EMFJ used in combination with FCZ showed synergistic effect with FICI values ≤0.5. The Eth-EMFJ/FCZ combination inhibited the growth, adherence, cellular surface hydrophobicity, hyphae, and biofilm formation of FCZ-resistant <i>Candida albicans in vitro</i>. RNA-seq identified alterations in glycolysis (e.g. PGK1), cell wall (e.g. MNN22), and drug resistance genes (e.g. MDR1), suggesting their potential role in the Eth-EMFJ/FCZ synergy. <i>In vivo</i>, Eth-EMFJ/FCZ treatment protected vaginal mucosa by reducing fungal colonisation, irritation, and restoring keratinisation. In conclusion, the combination of Eth-EMFJ and FCZ may offer a promising therapeutic approach for managing VVC caused by FCZ-resistant <i>C. albicans</i>.