An Organoselenium Compound Induces Death in Cryptococcus gattii Yeast by Apoptosis and Necrosis and Shows Antifungal Efficacy in Galleria mellonella.

Cryptococcus gattii is an etiological agent of invasive pulmonary cryptococcosis in both immunocompetent and immunocompromised individuals. Current antifungal therapy is limited by toxicity, high cost, and emerging tolerance, supporting the need for new therapeutic alternatives. Although the organoselenium compound LQA_78 previously demonstrated antifungal activity against Cryptococcus neoformans, its effect on C. gattii remains unclear. Then, the aim of this work is to evaluate the antifungal activity of LQA_78 against C. gattii strains, its effects on virulence factors, and the underlying mechanisms of fungal cell death. Clinical isolates and morphotypes of C. gattii were subjected to susceptibility testing to determine inhibitory and fungicidal concentrations. Capsule thickness and permeability, melanin production, and laccase activity were assessed. Oxidative stress parameters, including reactive oxygen species (ROS) production, lipid peroxidation, glutathione (GSH) levels, and superoxide dismutase activity, were evaluated. Mitochondrial membrane potential, DNA fragmentation, and chromatin condensation were analyzed to investigate cell death pathways. In vivo efficacy was assessed using the Galleria mellonella infection model. LQA_78 inhibited fungal growth at concentrations comparable to fluconazole (2-32 μg/mL), increased capsule permeability without reduction in capsule thickness, and melanin production and laccase activity were significantly reduced. LQA_78, at higher concentrations (16-32 μg/mL), induced and increased plasma membrane permeability, lipid peroxidation, ROS accumulation, GSH depletion, reduced superoxide dismutase activity, mitochondrial dysfunction, DNA fragmentation, chromatin condensation, and phosphatidylserine externalization, indicating apoptosis- and necrosis-like cell death. In G. mellonella, nontoxic doses reduced the larvae mortality and fungal burden and increased hemocyte density. Therefore, the organoselenium LQA_78 demonstrates significant in vitro and in vivo antifungal activity against C. gattii, supporting its potential as a lead compound for cryptococcosis therapy.