Repurposing antipsychotic drugs into antifungal agents: Synergistic combinations of azoles and bromperidol derivatives in the treatment of various fungal infections
Repurposing antipsychotic drugs into antifungal agents: Synergistic combinations of azoles and bromperidol derivatives in the treatment of various fungal infections
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DOI：
10.1016/j.ejmech.2017.07.030
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发表时间：
2017-10-20
影响因子：
6.7
通讯作者：
Garneau-Tsodikova, Sylvie
中科院分区：
文献类型：
--
作者：
Holbrook, Selina Y. L.;Garzan, Atefeh;Garneau-Tsodikova, Sylvie
随着住院和免疫功能低下患者数量的持续上升，侵袭性真菌感染，如侵袭性念珠菌病和曲霉病，每年威胁着数百万患者的生命。唑类抗真菌药物是目前临床上使用最多的药物，具有广谱抗真菌活性和良好的口服生物利用度。然而，唑类抗真菌药有其自身的局限性，无法应对与真菌感染增加相关的挑战以及伴随的唑类耐药性的发展。探索涉及当前唑类和另一种药物的联合治疗已被证明是一种有前途的策略。氟哌啶醇及其衍生物溴哌啶醇最初是作为抗精神病药发现的。在此，我们合成并报告了一系列的溴哌利多衍生物和它们的协同抗真菌相互作用的组合与目前的各种唑类抗真菌剂对广泛的面板的真菌病原体。我们进一步选择两种代表性的组合，并通过进行时间杀灭试验来确认抗真菌协同作用。此外，我们评估了所选组合破坏真菌生物膜的能力。最后，我们用代表性组合对三种哺乳动物细胞系进行哺乳动物细胞毒性测定。(C)2017 Elsevier Masson SAS。All rights reserved.
As the number of hospitalized and immunocompromised patients continues to rise, invasive fungal infections, such as invasive candidiasis and aspergillosis, threaten the life of millions of patients every year. The azole antifungals are currently the most prescribed drugs clinically that display broad-spectrum antifungal activity and excellent oral bioavailability. Yet, the azole antifungals have their own limitations and are unable to meet the challenges associated with increasing fungal infections and the accompanied development of resistance against azoles. Exploring combination therapy that involves the current azoles and another drug has been shown to be a promising strategy. Haloperidol and its derivative, bromperidol, were originally discovered as antipsychotics. Herein, we synthesize and report a series of bromperidol derivatives and their synergistic antifungal interactions in combination with a variety of current azole antifungals against a wide panel of fungal pathogens. We further select two representative combinations and confirm the antifungal synergy by performing time-kill assays. Furthermore, we evaluate the ability of selected combinations to destroy fungal biofilm. Finally, we perform mammalian cytotoxicity assays with the representative combinations against three mammalian cell lines. (C) 2017 Elsevier Masson SAS. All rights reserved.