Synergistic Antifungal Activity of Pentamidine and Auranofin Against Multidrug-Resistant Candida auris.

BACKGROUND

Candida auris is a significant clinical concern due to its ability to cause outbreaks in healthcare settings and its common resistance to current treatments. This highlights the need for alternative therapies. Drug repurposing offers a promising approach, and the combination of pentamidine (antiprotozoal) and auranofin (anti-rheumatic) has shown potential antifungal activity against Candida species, including C. auris. This study aimed to evaluate the antifungal activity of pentamidine and auranofin, both individually and in combination, against C. auris.

METHODS

Minimum Inhibitory Concentrations (MICs) were determined following CLSI guidelines, and drug interactions were assessed using the checkerboard microdilution method. Additional evaluations included growth inhibition, antibiofilm activity, cell damage, sorbitol protection, and efflux pump inhibition. Nucleotide leakage and cell membrane permeability were analyzed using biochemical assays. In vivo efficacy was tested using a Tenebrio molitor larvae model infected with C. auris.

RESULTS

The MICs of pentamidine against C. auris ranged from 16 to 128 μg/mL, showing fungicidal activity. The combination with auranofin had a synergistic effect (FICI: 0.37) and exhibited a fungistatic effect in growth inhibition assays. Auranofin was most effective at inhibiting biofilm formation. Pentamidine impaired mitochondrial function, leading to cellular respiration issues and membrane damage. Efflux pump assays indicated activation by both drugs, potentially influencing resistance. In vivo tests showed both drugs significantly improved survival rates in infected larvae compared to fluconazole.

CONCLUSION

In conclusion, pentamidine and auranofin, either individually or in combination, are promising treatments for C. auris and warrant further research into optimal dosing and combination strategies.