Abstract / Summary
Introduction Candida albicans is the predominant etiological agent of vulvovaginal candidiasis (VVC). Fluconazole (FLU), a first-line azole antifungal agent, has encountered growing resistance among vaginal isolates of C. albicans due to prolonged, high-dose clinical administration. The development of such drug resistance arises from the synergistic interplay of multiple factors, with key mechanisms including enhanced biofilm formation, overexpression of drug efflux pump genes, and structural alterations in target enzymes driven by mutations in the ERG11 gene. Lactobacilli , the dominant commensal probiotics in the vaginal microbiota, are known to inhibit biofilm formation by C. albicans , a process closely linked to the development of antifungal resistance. Consequently, vaginal lactobacilli may serve as a pharmacological adjuvant to enhance the antifungal efficacy of fluconazole against C. albicans . While existing research has primarily focused on the inhibitory effects of Lactobacilli on C. albicans proliferation, investigations into their impact on antifungal resistance remain limited. Methods We investigate the impact of vaginal L. paragasseri on fluconazole-resistance phenotypes in a subset of clinical fluconazole-resistant C. albicans isolates. Guided by established fluconazole-resistance mechanisms, we first screened fluconazole resistant C. albicans isolates by assessing biofilm formation capacity, drug efflux pump gene expression, and ERG11 gene mutations and mRNA expression. Next, analysis of the vaginal Lactobacillus composition in VVC patients and healthy controls showed a nominal, non-significant trend toward lower L. paragasseri detection in VVC-affected women. Motivated by this trend and by prior evidence that Lactobacilli can modulate antifungal-resistance phenotypes, we examined whether L. paragasseri modulates fluconazole-resistance in clinically derived C. albicans isolates through functional assays. Subsequent functional assessments, including standard antifungal susceptibility testing, biofilm formation assays, and drug efflux pump gene expression analyses. Results Vaginal L. paragasseri can attenuate fluconazole-resistant phenotypes in the tested subset of clinical fluconazole-resistant C. albicans isolates. In a murine vulvovaginal candidiasis model, adjunctive treatment with L. paragasseri provided adjuvant benefit when added to fluconazole therapy, reducing vaginal C. albicans colonization and alleviating infection-associated tissue damage. These in-vivo observations constitute preliminary pre-clinical evidence. Discussion These findings demonstrate that vaginal L. paragasseri holds promising potential as a probiotic adjunctive therapy for C. albicans -induced VVC, offering novel insights for the development of alternative antifungal therapeutic strategies.