JVATiTD - Articles

Abstract

Background: Sporotrichosis is a fungal infection caused by species of the Sporothrix schenckii complex. Antifungal treatment with itraconazole and amphotericin B is limited by increasing resistance, adverse effects, and prolonged treatment courses, highlighting the need for novel antifungal strategies. Methods: The antifungal activity of seven antimicrobial peptides derived from arthropod toxins against Sporothrix species was evaluated: six synthetic peptides derived from the spider Lycosa erythrognatha toxin and one peptide isolated from apitoxin (melittin). Minimum inhibitory concentrations (MICs) and minimum fungicidal concentrations (MFCs) were determined. Mechanistic assays were performed to investigate membrane damage, oxidative stress induction, and interactions with ergosterol and the fungal cell wall. Synergistic activity with itraconazole was assessed, and the effect of melittin on selected virulence factors was studied. To explore potential therapeutic applications, a melittin-based formulation for local (intralesional) usage was developed, and its cytotoxicity was tested in HEK-293 and HepG2 cell lines, as well as its short-term safety in murine models. Results: All peptides inhibited S. schenckii and S. brasiliensis, with MIC and MFC values ranging from 0.5 to 32 µM. Melittin displayed the strongest antifungal effect, acting predominantly through a membranolytic mechanism associated with oxidative stress. Combined with itraconazole, melittin demonstrated synergistic activity against both species. Melittin selectively reduced pyomelanin production, while urease activity remained unaffected. The melittin-based formulation showed lower cytotoxicity compared to melittin alone, and subcutaneous administration in mice was well tolerated at the lowest dose tested (0.1 mg/kg). Conclusion: Melittin exhibits potent antifungal activity against Sporothrix spp. and synergism with itraconazole, supporting further investigation as an antifungal candidate. Although therapeutic efficacy was not evaluated in infected animal models, the development of a safer melittin-based formulation provides a proof-of-concept foundation for future studies focusing on the local treatment of cutaneous sporotrichosis.