Moxidectin elevates Candida albicans ergosterol levels to synergize with polyenes against oral candidiasis

Candida albicans, the most common opportunistic pathogenic fungus, is also the main pathogenic organism for oral candidiasis. This condition is particularly prevalent among the elderly, children, and individuals undergoing radiotherapy or suffering from HIV. The lack of new antifungal drugs, and drug resistance coupled with the side effects of current antifungal agents have increased the challenges of clinical antifungal therapies. Polyenes, including amphotericin B and nystatin, are clinical fungicidal drugs, however, their side effects and low solubility have limited their clinical applications. Here, we identified that moxidectin, a novel approved antiparasitic agent, could synergize with both amphotericin B and nystatin to inhibit the growth and biofilm formation of Candida albicans including 60 clinical isolates. The transcriptome and RT-PCR analysis indicated that moxidectin activated the biosynthesis pathway of ergosterol, the direct target of polyenes, further being verified by the loss of the synergistic activities with polyenes against ergosterol pathway mutants, including Δ/Δerg3, Δ/Δerg11 and Δ/Δerg3 Δ/Δerg11. Moxidectin was then confirmed to elevate the ergosterol biosynthesis levels of C. albicans and enhance the binding between cells and polyenes. In a mouse oral candidiasis model, moxidectin combined with low dosages of polyenes to significantly reduce the infection area, colonization of C. albicans and the inflammatory degree of tongue mucosa. Our study originally demonstrated that moxidectin could activate the ergosterol biosynthesis then elevate the ergosterol contents to enhance the antifungal effects of polyenes against C. albicans and its infections. Moxidectin can serve as the candidate potentiator of polyenes for further clinical practice. KEY POINTS: • Moxidectin synergized with polyenes against Candida albicans. • Moxidectin activated the ergosterol biosynthesis of Candida albicans. • Moxidectin combined with polyenes to effectively combat oral candidiasis in mice.