Activity of Metal-Azole Complexes Against Biofilms of Candida albicans and Candida glabrata

Background: Onychomycosis is a chronic nail infection caused by fungi frequently resistant to antifungal treatments. Recalcitrance in nail infections is a result of reduced antifungal penetration due to biofilm formation, combined with poor patient compliance with the treatment, which can be as long as 18 months. Objective: Metal-drug complexation is a widely used strategy to increase drug efficacy. Therefore, the aim of this work was to evaluate the antifungal and anti-biofilm activity of several metal-azole complexes against Candida albicans and Candida glabrata. Methods: Susceptibility assays and scanning electron microscopy were performed to determine the anti-biofilm activity of eight metal-azole complexes in vitro and ex-vivo, using human nail fragments. Results: In vitro susceptibility assays showed that complexation of both Au(I) and Zn(II) to clotrimazole and ketoconazole improved the anti-biofilm activity compared to the azole alone. Using an ex-vivo model of biofilm formation on fragments of human nails, we also demonstrate the improved efficacy of metal-azole complexes against biofilms of C. albicans and C. glabrata that resembles the onychomycosis structure. Noteworthy, biofilms of C. glabrata were more susceptible to the optimized complexes than those of C. albicans. Conclusion: In conclusion, metal-azole complexes used in this work show promising anti-biofilm activity and further clinical studies should confirm its potential for the treatment of Candida-associated onychomycosis.