Identification of Ermiao Fang Jiawei extract as potential synergist against fluconazole-resistant Candida albicans in vitro 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 Atractylodis rhizoma, Phellodendri chinensis cortex, Cnidii fructus, and Charred Sanguisorbae radix. 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 Candida albicans in vitro. 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. In vivo, 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 C. albicans.