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磷霉素对……的抑制作用

Inhibitory Effects of Fosmidomycin Against .

作者信息

Wang Sen, Li Muxiao, Luo Xiaoying, Yu Long, Nie Zheng, Liu Qin, An Xiaomeng, Ao Yangsiqi, Liu Qin, Chen Jiaxu, Tian Yu, Zhao Junlong, He Lan

机构信息

State Key Laboratory of Agricultural Microbiology, College of Veterinary Medicine, Huazhong Agricultural University, Wuhan, China.

Key Laboratory of Preventive Veterinary Medicine in Hubei Province, Wuhan, China.

出版信息

Front Cell Dev Biol. 2020 Apr 28;8:247. doi: 10.3389/fcell.2020.00247. eCollection 2020.

Abstract

, the main pathogen causing human babesiosis, has been reported to exhibit resistance to the traditional treatment of azithromycin + atovaquone and clindamycin + quinine, suggesting the necessity of developing new drugs. The methylerythritol 4-phosphate (MEP) pathway, a unique pathway in apicomplexan parasites, was shown to play a crucial function in the growth of . In the MEP pathway, 1-deoxy-D-xylulose 5-phosphate reductoisomerase (DXR) is a rate-limiting enzyme and fosmidomycin (FSM) is a reported inhibitor for this enzyme. DXR has been shown as an antimalarial drug target, but no report is available on DXR (BmDXR). Here BmDXR was cloned, sequenced, analyzed by bioinformatics, and evaluated as a potential drug target for inhibiting the growth of . Drug assay was performed by adding different concentrations of FSM in culture. Rescue experiment was done by supplementing 200 μM isopentenyl pyrophosphate (IPP) or 5 μM geranylgeraniol (GG-ol) in the culture medium together with 5 μM FSM or 10 μM diminazene aceturate. The results indicated that FSM can inhibit the growth of in culture with an IC50 of 4.63 ± 0.12 μM, and growth can be restored by both IPP and GG-ol. Additionally, FSM is shown to inhibit the growth of parasites by suppressing the DXR activity, which agreed with the reported results of other apicomplexan parasites. Our results suggest the potential of DXR as a drug target for controlling and that FSM can inhibit the growth of .

摘要

已报道,引起人类巴贝斯虫病的主要病原体对阿奇霉素+阿托伐醌和克林霉素+奎宁的传统治疗表现出抗性,这表明开发新药的必要性。甲基赤藓糖醇4-磷酸(MEP)途径是顶复门寄生虫中的独特途径,已证明其在的生长中起关键作用。在MEP途径中,1-脱氧-D-木酮糖5-磷酸还原异构酶(DXR)是限速酶,磷霉素(FSM)是该酶的报道抑制剂。DXR已被证明是抗疟药物靶点,但关于DXR(BmDXR)尚无报道。在此,克隆了BmDXR,进行了测序,通过生物信息学进行了分析,并评估其作为抑制生长的潜在药物靶点。通过在培养物中添加不同浓度的FSM进行药物测定。通过在培养基中补充200μM异戊烯基焦磷酸(IPP)或5μM香叶基香叶醇(GG-ol)以及5μM FSM或10μM乙酰氨基阿维菌素进行挽救实验。结果表明,FSM可抑制培养物中的生长,IC50为4.63±0.12μM,IPP和GG-ol均可恢复生长。此外,FSM通过抑制DXR活性来抑制寄生虫生长,这与其他顶复门寄生虫的报道结果一致。我们的结果表明DXR作为控制的药物靶点的潜力,并且FSM可抑制的生长。

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