FDA Approved Drug Library Screening Identifies Robenidine as a Repositionable Antifungal
FDA Approved Drug Library Screening Identifies Robenidine as a Repositionable Antifungal
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FDA 批准的药物库筛选确定罗苯尼定是一种可重新定位的抗真菌药物
DOI：
10.3389/fmicb.2020.00996
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发表时间：
2020-06-03
影响因子：
5.2
通讯作者：
Wang, Hui
中科院分区：
文献类型：
--
作者：
Mei, Yikun;Jiang, Tong;Wang, Hui
由于病原性真菌感染的患病率不断增加，全球范围内出现抗真菌耐药的临床分离株，以及可用的抗真菌药物有限，开发新的抗真菌策略势在必行。在这项研究中，我们筛选了1068种FDA批准的药物库，以确定具有广谱抗真菌活性的药物。本试验筛选出一种广泛用于治疗家禽和家兔球虫感染的抗球虫药--氯苯胍。生理浓度的氯苯胍（8 μ M）能够显着抑制酵母细胞的生长，发酵和生物膜形成的白色念珠菌-最广泛的研究人类真菌病原体。此外，我们观察到该化合物对氟康唑耐药临床分离株的广谱抗真菌活性。白色念珠菌，阿萨广泛的其他临床相关的真菌病原体。有趣的是，robenidine-treatedC.白念珠菌细胞对多种细胞壁应激物高度敏感，透射电镜（TEM）分析细胞壁结构表明氯苯胍对白念珠菌细胞壁有严重损伤，提示该化合物可能作用于细胞壁完整性信号通路。事实上，在氯苯胍处理后，我们发现细胞壁完整性标志物Mkc 1的磷酸化呈剂量依赖性增加，其在长时间暴露后降低。最后，我们通过RNA-seq和qPCR提供证据，Mkc 1的下游转录因子Rlm 1可能是氯苯胍的潜在靶点。因此，我们的数据表明，robenidine，FDA批准的抗球虫药物，显示了一个有前途的和广泛有效的抗真菌策略，并代表了一个潜在的可重新定位的候选人用于治疗真菌感染。
Due to the increasing prevalence of pathogenic fungal infections, the emergence of antifungal resistant clinical isolates worldwide, and the limited arsenal of available antifungals, developing new antifungal strategies is imperative. In this study, we screened a library of 1068 FDA-approved drugs to identify hits that exhibit broad-spectrum antifungal activity. Robenidine, an anticoccidial agent which has been widely used to treat coccidian infections of poultry and rabbits, was identified in this screen. Physiological concentration of robenidine (8 mu M) was able to significantly inhibit yeast cell growth, filamentation and biofilm formation ofCandida albicans- the most extensively studied human fungal pathogen. Moreover, we observed a broad-spectrum antifungal activity of this compound against fluconazole resistant clinical isolates ofC. albicans,as well asa wide range of other clinically relevant fungal pathogens. Intriguingly, robenidine-treatedC. albicanscells were hypersensitive to diverse cell wall stressors, and analysis of the cell wall structure by transmission electron microscopy (TEM) showed that the cell wall was severely damaged by robenidine, implying that this compound may target the cell wall integrity signaling pathway. Indeed, upon robenidine treatment, we found a dose dependent increase in the phosphorylation of the cell wall integrity marker Mkc1, which was decreased after prolonged exposure. Finally, we provide evidence by RNA-seq and qPCR that Rlm1, the downstream transcription factor of Mkc1, may represent a potential target of robenidine. Therefore, our data suggest that robenidine, a FDA approved anti-coccidiosis drug, displays a promising and broadly effective antifungal strategy, and represents a potentially repositionable candidate for the treatment of fungal infections.