Institute of Parasitology, University of Berne, Berne, Switzerland.
J Antimicrob Chemother. 2011 May;66(5):1029-35. doi: 10.1093/jac/dkr029. Epub 2011 Feb 10.
The protozoan parasite Giardia lamblia causes the intestinal disease giardiasis, which may lead to acute and chronic diarrhoea in humans and various animal species. For treatment of this disease, several drugs such as the benzimidazole albendazole, the nitroimidazole metronidazole and the nitrothiazolide nitazoxanide are currently in use. Previously, a G. lamblia nitroreductase 1 (GlNR1) was identified as a nitazoxanide-binding protein. The aim of the present project was to elucidate the role of this enzyme in the mode of action of the nitro drugs nitazoxanide and metronidazole.
Recombinant GlNR1 was overexpressed in both G. lamblia and Escherichia coli (strain BL21). The susceptibility of the transfected bacterial and giardial cell lines to nitazoxanide and metronidazole was analysed.
G. lamblia trophozoites overexpressing GlNR1 had a higher susceptibility to both nitro drugs. E. coli were fully resistant to nitazoxanide under both aerobic and semi-aerobic growth conditions. When grown semi-aerobically, bacteria overexpressing GlNR1 became susceptible to nitazoxanide.
These findings suggest that GlNR1 activates nitro drugs via reduction yielding a cytotoxic product.
原生动物寄生虫蓝氏贾第鞭毛虫可引起肠道疾病贾第虫病，这可能导致人类和各种动物物种出现急性和慢性腹泻。为治疗这种疾病，目前使用几种药物，如苯并咪唑阿苯达唑、硝基咪唑甲硝唑和硝基噻唑啉硝唑。此前，鉴定出蓝氏贾第鞭毛虫硝基还原酶 1（GlNR1）是一种硝唑的结合蛋白。本项目的目的是阐明该酶在硝基药物硝唑和甲硝唑作用模式中的作用。
在蓝氏贾第鞭毛虫和大肠杆菌（BL21 株）中过表达重组 GlNR1。分析转染的细菌和贾第虫细胞系对硝唑和甲硝唑的敏感性。
过表达 GlNR1 的蓝氏贾第鞭毛虫滋养体对两种硝基药物的敏感性更高。在需氧和半需氧生长条件下，大肠杆菌对硝唑完全耐药。当在半需氧条件下生长时，过表达 GlNR1 的细菌对硝唑变得敏感。
这些发现表明 GlNR1 通过还原生成细胞毒性产物来激活硝基药物。
