Repurposing tafenoquine as a potent antifungal agent against Candida haemulonii sensu stricto

The rise in fungal infections caused by multidrug-resistant pathogens like Candida haemulonii sensu stricto presents a significant global health challenge. The common resistance to current treatments underscores the urgency to explore alternative therapeutic strategies, including drug repurposing. To assess the potential of repurposing tafenoquine, an antimalarial agent, for antifungal use against C. haemulonii sensu stricto. The efficacy of tafenoquine was tested using in vitro assays for minimum inhibitory concentration (MIC), minimum fungicidal concentration, biofilm inhibition, cell damage, cell membrane integrity, nucleotide leakage, sorbitol protection assay, and efflux pump inhibition. The compound's cytotoxicity was assessed through a haemolysis assay, and in vivo safety and efficacy were tested using Tenebrio molitor larvae. Tafenoquine exhibited potent fungicidal activity against C. haemulonii sensu stricto with an MIC of 4 mg/L and significantly inhibited biofilm formation by 60.63%. Tafenoquine also impaired mitochondrial functionality, leading to compromised cellular respiration. Despite these effects, tafenoquine did not cause significant protein leakage, indicating a distinct mechanism from membrane-targeting agents. In vivo study confirmed tafenoquine's non-toxic profile with no observed haemolysis or acute toxicity in the T. molitor model. During antifungal treatment with tafenoquine, a survival rate of approximately 60% was observed after 3 days. The findings of this study highlight tafenoquine's potential as a promising candidate for antifungal drug repurposing, especially against C. haemulonii sensu stricto. Its effectiveness in inhibiting fungal growth and biofilm formation underscores its viability for further clinical development as a novel antifungal therapy.