Ambroxol Hydrochloride Combined with Fluconazole Reverses the Resistance of Candida albicans to Fluconazole

Abstract

In this study, we found that ambroxol hydrochloride (128 μg/mL) exhibits synergistic antifungal effects in combination with fluconazole (2 μg/mL) against resistant planktonic <i>Candida albicans</i> (<i>C. albicans</i>) cells. This combination also exhibited synergistic effects against resistant <i>C. albicans</i> biofilms in different stages (4, 8, and 12 h) according to the microdilution method. <i>In vitro</i> data were further confirmed by the success of this combination in treating <i>Galleria mellonella</i> infected by resistant <i>C. albicans</i>. With respect to the synergistic mechanism, our result revealed that ambroxol hydrochloride has an effect on the drug transporters of resistant <i>C. albicans</i>, increasing the uptake and decreasing the efflux of rhodamine 6G, a fluorescent alternate of fluconazole. This is the first study to investigate the <i>in vitro</i> and <i>in vivo</i> antifungal effects, as well as the possible synergistic mechanism of ambroxol hydrochloride in combination with fluconazole against resistant <i>C. albicans</i>. The results show the potential role for this drug combination as a therapeutic alternative to treat resistant <i>C. albicans</i> and provide insights into the development of antifungal targets and new antifungal agents.