In-depth evaluation of the antifungal effect of melittin against Candida albicans and therapeutic prospecting in a rat model of vulvovaginal candidiasis

The increase in the number and severity of patients with fungal infections, such as those caused by Candida spp. , has become a public health problem. The limited therapeutic arsenal and increasing resistance to antifungal agents highlight the need for development of new alternative therapeutics. The antimicrobial peptide (AMP) melittin, the main component of Apis mellifera venom, stands out as a promising prototype. The present study aimed to investigate the antifungal properties of melittin against C. albicans in vitro. Furthermore, this study evaluated the therapeutic effects of a melittin-based vaginal cream formulation in a model of vulvovaginal candidiasis (VVC) in rats. The results obtained in vitro revealed a significant to moderate fungicidal activity of melittin against clinical isolates of C. albicans recovered from vaginal secretions and oral cavity (Minimum Fungicidal Concentration (MFC) in range of 4 and 32 µM). Melittin was able to inhibit important virulence factors in C. albicans such as yeast-to-hyphae transition and biofilm formation. The combination of melittin with azoles resulted in a synergistic effect and this peptide reduce the resistance to ketoconazole and fluconazole in an azole-resistant C. albicans lineage. Finally, in vivo results showed that the vaginal cream supplemented with 1.0 % melittin was able to treat C. albicans -induced VVC in rats, resulting in mycological cure after six days of treatment. Therefore, the study suggests that melittin has important antifungal properties and may be explored for development of new topical formulations for the treatment of VVC. • 1 Melittin displays potent antifungal activity against clinical isolates of Candida albicans. • 2. Effective against biofilms and yeast-to-hyphae transition. • 3. Pre-treatment with melittin sensitized azole-resistant C. albicans strains. • 4. A 1 % melittin topical cream led mycological cure in a rat model of VVC.