聚乙二醇化多粘菌素E对革兰阴性菌感染的治疗效果及降低肾毒性的作用

Therapeutic efficacy of pegylated polymyxin E in the treatment of infection induced by gramnegative bacteria and the effect of reducing nephrotoxicity

多粘菌素E(polymyxin E,PME)能有效治疗耐药性革兰阴性菌引发的各类感染,但是其明显的肾脏毒性却严重限制了该药物的临床应用。本研究采用化学合成的方法制备了聚乙二醇2000单甲醚-多粘菌素E(m PEG2K-PME),并对其进行了初步表征。在体外抗菌实验和细胞毒性实验的基础上,进一步构建小鼠大肠杆菌腹腔感染模型,考察m PEG2K-PME对腹腔感染小鼠的治疗效果及其对肾组织的毒性作用。结果表明:m PEG2K-PME在体外环境下对大肠杆菌具有明显的抑制作用,对HK-2细胞的毒性降低;在体内对小鼠腹腔感染具有良好的治疗效果,肾毒性明显降低,有望开发成高效低毒的新型制剂。

Polymyxin E shows effective treatment of the infection induced by resistant gramnegative bacteria, but its nephrotoxicity severely limits the clinical application of this drug. In this work, methoxypolyethylene glycols 2000 （mPEG2K）-polymyxin E （PME） was synthesized via chemical grafting reaction and had been characterized. The antimicrobial activity and cytotoxicity of mPEG2K-PME in vitro were investigated on Escherichia coli and HK-2 cells, separately. Intra-abdominal infection model was further established in order to study the therapeutic effect and the toxic effect on kidney of mice. The results showed that mPEG2K-PME exhibited significant inhibitory effect on Escherichia coli and had a lower toxicity on HK-2 cells in vitro. At the same time, mPEG2K-PME had a good efficacy in the treatment of Escherichia coli infected mice in vivo. Moreover, nephrotoxicity caused by mPEG2K-PME was significantly reduced compared to free PME. mPEG2K-PME is promising in development of new preparations with high efficiency and low toxicity.