State Key Laboratory of Oral Diseases and National Clinical Research Center for Oral Diseases, West China Hospital of Stomatology, Sichuan University, No.14, 3rd Section of Ren Min Nan Rd., Chengdu, 610041, Sichuan, China.
Department of Cariology and Endodontics, West China Hospital of Stomatology, Sichuan University, Chengdu, 610041, China.
Appl Microbiol Biotechnol. 2019 Aug;103(16):6701-6709. doi: 10.1007/s00253-019-09960-3. Epub 2019 Jun 14.
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.
白色念珠菌在免疫功能低下的个体中可导致高死亡率，但不断增加的耐药性挑战了当前的抗真菌治疗方法。氟奋乃静（FPZ），一种常用的抗精神病药物，可诱导白色念珠菌中药物外排泵的表达，从而可能干扰氟康唑（FLC）和两性霉素 B（AmB）等抗真菌药物的治疗效果。在这里，我们研究了 FLC/FPZ 和 AmB/FPZ 联合治疗体外和系统性念珠菌病小鼠模型的效果。当补充 FPZ 时，FLC 的抗真菌活性显著降低。FPZ 拮抗 FLC 对与白色念珠菌毒力相关的基因 ALS3 和 HWP1 表达的抑制作用。然而，FPZ 增强了白色念珠菌对 AmB 的敏感性，并以协同方式进一步下调 ALS3 和 HWP1 的表达。FPZ 还增强了 ERG11 的基因表达，ERG11 是一种与 FLC 和 AmB 活性相关的关键甾醇生物合成途径基因。在我们的哺乳动物感染模型中，与单独使用 FLC 相比，用 FLC/FPZ 治疗的小鼠的生活状态明显较差，肾脏和大脑中的真菌负荷增加。相反，联合应用 AmB/FPZ 显著提高了感染小鼠的存活率，减轻了体重减轻，并降低了器官中的真菌负担。这些数据表明，FPZ 拮抗了 FLC 的治疗效果，但增强了 AmB 在念珠菌病治疗中的抗真菌活性。
