Fluphenazine antagonizes with fluconazole but synergizes with amphotericin B in the treatment of candidiasis
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Candida albicans causes a high mortality rate in immunocompromised individuals, but the increased drug resistance challenges the current antifungal therapeutics. Fluphenazine (FPZ), a commonly used antipsychotic medication, can induce the expression of drug efflux pumps in C. albicans and, thus, may interfere with the therapeutic efficacy of antifungals, such as fluconazole (FLC) and amphotericin B (AmB). Here, we investigated the combined effects of FLC/FPZ and AmB/FPZ against C. albicans in vitro and in a systemic candidiasis mouse model. The antifungal activity of FLC was significantly reduced when supplemented with FPZ. The inhibitory effects of FLC on the expression of the Candida virulence-related genes ALS3 and HWP1 were antagonized by FPZ. However, FPZ enhanced the susceptibility of C. albicans to AmB and further downregulated the expression of ALS3 and HWP1 in a synergistic manner with AmB. FPZ also enhanced the gene expression of ERG11, a key gene of the ergosterol biosynthesis pathway that has been associated with the activities of both FLC and AmB. In our mammalian infection model, mice treated with FLC/FPZ showed notably poor living status and increased fungal burden in their kidneys and brains compared with those treated with FLC alone. Conversely, the combined application of AmB/FPZ significantly improved the survival rate, attenuated the weight loss and reduced the organ fungal burdens of the infected mice. These data suggest that FPZ antagonized the therapeutic efficacy of FLC but enhanced the antifungal activity of AmB in the treatment of candidiasis.
KeywordsDrug interactions Ergosterol Antipsychotics Virulence factor Systemic candidiasis
This work was supported by the National Natural Science Foundation of China (NSFC, 81870778, 81771099, 81600858, 81500842) and research grants from the Department of Science and Technology of Sichuan Province (2018SZ0121, 2016JY0006).
Compliance with ethical standards
Conflict of interest
The authors declare that they have no conflict of interest.
All animal protocols in this study were conducted in strict accordance with the guidelines of Ethics Committee of West China Hospital of Stomatology, Sichuan University, and the ethics approval was obtained from this institution (license number WCHSIRB-D-2017-134). All efforts were made to minimize suffering and ensure the highest ethical and humane standards.
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