Synergistic effects of geldanamycin with fluconazole are associated with reactive oxygen species in Candida tropicalis resistant to azoles and amphotericin B

Abstract

With a significant increase in the incidence of system invasive fungal infections, the limited antifungal drugs and increased frequency of cross-resistance make it necessary to explore new and effective therapeutic strategies. Combination drug therapy has become one widely used choice to alleviate this problem. Geldanamycin (GdA), as an inhibitor of Hsp90, displayed broad antifungal activity when combined with fluconazole. However, due to its cytotoxicity, the dose and duration of GdA is limited. In this study, we observed the effect of fluconazole plus GdA on Candida tropicalis resistant to azoles and amphotericin B. The results showed that this synergism led to a decrease in growth and survival rate. In addition, fluconazole combined with GdA caused mitochondrial depolarisation, disruption of plasma membrane integrity and multinucleated morphology. However, the supplement of a reactive oxygen species (ROS) scavenger, N-acetylcysteine (NAC), rescued the above phenotypes. This study indicated that the oxidative stress mediated by fluconazole plus GdA played an important role in the antifungal activity, and targeting oxidative stress might extend target choices to treat fungal infections.

Keywords:

• Candida tropicalis
• fluconazole
• geldanamycin
• ROS

Acknowledgements

We are grateful to Dr. Meng Xiao (Peking Union Medical College Hospital) and Dr. Wei Liu (Peking University First Hospital) for the generous gift of strains.

Disclosure statement

No potential conflict of interest was reported by the authors.

Additional information

Funding

This work was supported by Zhejiang Provincial Natural Science Foundation of China under Grant No. LQ18C010003 to Chang Jia, and No. LQ18H150003 to Ke Xu.