Silver(I) and Copper(II) complexes of 1,10-phenanthroline-5,6-dioninhibitazole-resistant clinical isolates.

Abstract

BACKGROUND: 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 theandantifungal properties of [Cu(phendione)3](ClO4)2.4H2O (Cu-phendione) and [Ag(phendione)2]ClO4 (Ag-phendione) againstisolates from domestic felines in endemic regions. METHODS: Six clinical isolates ofobtained 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 toMinimum 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)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 againstsaprophytic and parasitic phases. Additionally,antifungal efficacy was assessed usinglarvae 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")clinical isolates. Notably, MFC values were equal to or at most twice the MICs, indicating a fungicidal profile, even against itraconazole-resistant strains.treated groups exhibited higher values than thegroup (6.0 days) while all compounds provided larvae mean survival higher than the itraconazole treated group ( > 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-resistantisolates 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.