The antifungal activity of the laccase inhibitor DMSA against Cryptococcus neoformans is linked to the perturbation of histidine biosynthesis

Current antifungals—polyenes, flucytosine, and azoles—are limited by toxicity and resistance, underscoring the need for new agents. This study evaluated dimercaptosuccinic acid (DMSA), beginning with its effect on the virulence factor laccase.

DMSA showed broad-spectrum activity against standard (H99, B3501) and clinical strains, with MIC values of 32–64 μg/mL. It inhibited laccase (IC₅₀ = 43.98 μM; Km = 0.547 mM with L-dopa) and impaired multiple virulence factors, including capsule formation (43.2% reduction in H99), urease activity (68.6% inhibition in H99 and 53.4% in B3501), as well as biofilm formation and its metabolic activity. In a Galleria mellonella infection model, although survival was not significantly improved, DMSA reduced fungal burden by 30% (P < 0.05), supported by histology and CFU counts.