Novel targets and potential therapeutic approaches for chromoblastomycosis: phosphatase/peptidase inhibitors and metal-based compounds containing 1,10-phenanthroline

Chromoblastomycosis (CBM) is a chronic, debilitating subcutaneous mycosis that remains a major therapeutic challenge due to its limited responsiveness to conventional antifungal agents. Our research group investigated key cellular mechanisms underlying fungal virulence, persistence, and resistance, revealing that CBM-associated fungi can exhibit ectophosphatase and calcineurin activities, secrete aspartic and metallo-type peptidases, and form highly structured biofilms that reinforce their chronic behaviour and tolerance to treatment. Targeted inhibition of these enzymatic systems using classical inhibitors of peptidases [e.g., human immunodeficiency virus (HIV) aspartic peptidase inhibitors], acid phosphatases (e.g., sodium orthovanadate), and calcineurin (e.g., tacrolimus and cyclosporine A) markedly impaired fungal growth, morphogenesis, biofilm development, and/or host-cell interactions, underscoring their potential roles in key fungal biological processes and infection establishment. Furthermore, coordination compounds incorporating transition metals (e.g., silver) and 1,10-phenanthroline-derived ligands demonstrated potent antifungal efficacy against CBM-associated fungi and may interfere with key physiological and virulence-associated pathways. Collectively, these findings advance the understanding of CBM fungal pathophysiology, unveiling novel molecular targets and highlighting opportunities for alternative therapeutic strategies and antifungal drug development.