Melittin, an arthropod venom peptide, potently inhibits *Sporothrix* fungi and synergizes with itraconazole

The global incidence of sporotrichosis, a fungal infection caused by species of the Sporothrix schenckii complex, is rising. Current antifungal treatments, primarily itraconazole and amphotericin B, face significant limitations due to increasing drug resistance, severe adverse effects, and prolonged treatment durations. This necessitates the urgent discovery of novel antifungal agents. Antimicrobial peptides (AMPs), particularly those derived from arthropod venoms, represent a promising class of compounds with distinct mechanisms of action that could circumvent existing resistance pathways.

Researchers evaluated the antifungal activity of seven antimicrobial peptides derived from arthropod toxins against Sporothrix schenckii and S. brasiliensis. Six synthetic peptides were derived from the spider Lycosa erythrognatha toxin, and one, melittin, was isolated from apitoxin. Minimum inhibitory concentrations (MICs) and minimum fungicidal concentrations (MFCs) were determined. Mechanistic assays investigated membrane damage, oxidative stress induction, and interactions with ergosterol and the fungal cell wall. Synergistic activity with itraconazole was assessed. The effect of melittin on virulence factors like pyomelanin and urease was studied. A melittin-based formulation for local (intralesional) usage was developed, and its cytotoxicity was tested in HEK-293 and HepG2 cell lines, with short-term safety evaluated in murine models via subcutaneous administration at 0.1 mg/kg.

All seven tested peptides demonstrated inhibitory activity against both S. schenckii and S. brasiliensis, with MIC and MFC values ranging from 0.5 to 32 µM. Among them, melittin exhibited the strongest antifungal effect, primarily through a membranolytic mechanism that was also associated with the induction of oxidative stress within fungal cells. When combined with itraconazole, melittin showed significant synergistic activity against both Sporothrix species, suggesting potential for combination therapy. > Melittin selectively reduced pyomelanin production, a key virulence factor, while leaving urease activity unaffected. The specially developed melittin-based formulation demonstrated lower cytotoxicity in HEK-293 and HepG2 cell lines compared to melittin alone. Furthermore, subcutaneous administration of this formulation in mice was well tolerated at the lowest dose tested (0.1 mg/kg), indicating a favorable initial safety profile for local application.