Silver(I) and Copper(II) complexes of 1,10-phenanthroline-5,6-dione inhibit Sporothrix brasiliensis azole-resistant clinical isolates

Background. Sporothrix brasiliensis is the principal etiological agent responsible for cat-transmitted zoonotic sporotrichosis, which is currently the most prevalent mycosis in South America—especially in Brazil—and is increasingly being reported in other regions. While itraconazole is the standard treatment, its use is limited by hepatotoxicity, high cost, and emerging reports of reduced susceptibility. Complexes of 1,10-phenanthroline-5,6-dione (phendione) with transition metals have previously shown promise as antifungal agents against bacteria, parasites, yeasts and filamentous fungi. This study investigates the in vitro and in vivo antifungal properties of [Cu(phendione)3](ClO4)2.4H2O (Cu-phendione) and [Ag(phendione)2]ClO4 (Ag-phendione) against S. brasiliensis isolates from domestic felines in endemic regions. Methods. Six clinical isolates of S. brasiliensis obtained from cutaneous lesions in six felines with laboratory-confirmed sporotrichosis from hyperendemic regions in the state of Rio de Janeiro, Brazil, were investigated. Selection was made according to in vitro Minimum Inhibitory Concentration (MIC) response criteria for itraconazole (‘‘wild type’’ WT = MIC ≤ 2 µg/mL; ‘‘non-wild type’’ NWT = MIC ≥ 4 µg/mL). The American Type Culture Collection (ATCC) S. brasiliensis MYA 4823 was included. The minimum inhibitory concentrations (MICs) and minimum fungicidal concentrations (MFCs) of phendione, its metal complexes, and simple silver and copper salts were evaluated against S. brasiliensis saprophytic and parasitic phases. Additionally, in vivo antifungal efficacy was assessed using Galleria mellonella larvae as a model. Results. Both metal complexes exhibited low MIC (0.3–5 µM) and MFC (0.3–10 µM) values against conidia and yeast forms of both WT (‘‘sensitive’’) and NWT (‘‘resistant’’) S. brasiliensis clinical isolates. Notably, MFC values were equal to or at most twice the MICs, indicating a fungicidal profile, even against itraconazole-resistant strains. Galleria mellonella treated groups exhibited higher values than the S. brasiliensis group (6.0 days) while all compounds provided larvae mean survival higher than the itraconazole treated group (p > 0.05). Cu-phendione was the compound that conferred the highest median survival (8.0 days). Discussion. Silver(I) and Copper(II) complexes of 1,10-phenanthroline-5,6-dione demonstrated both inhibitory and fungicidal activity against itraconazole-resistant S. brasiliensis isolates from diseased cats residing in the Brazilian hyperendemic region, highlighting their promise as novel antifungal agents. This finding is notable because drugs currently used for sporotrichosis treatment are characterized as fungistatic. This study provides data on alternative molecules that may be considered for future control of sporotrichosis, a zoonosis currently spreading throughout Latin America.