紫杉醇与黏菌素联用对大肠杆菌的协同作用及增效机制  

Synergism of paclitaxel and colistin against Escherichia coli and the synergistic mechanism

作　　者：胡雪勤 樊长健 何崎彪 刘佩仪 贺丹丹 吴华[1] 马小元 胡功政[1] 翟亚军 HU Xueqin;FAN Changjian;HE Qibiao;LIU Peiyi;HE Dandan;WU Hua;MA Xiaoyuan;HU Gongzheng;ZHAI Yajun(College of Veterinary Medicine,Henan Agricultural University,Zhengzhou 450046,China)

机构地区：[1]河南农业大学动物医学院,河南郑州450046

出　　处：《中国兽医学报》2025年第3期580-586,共7页Chinese Journal of Veterinary Science

基　　金：国家自然科学基金青年基金资助项目(32102716);国家自然科学基金资助项目(32273069)。

摘　　要：用微量肉汤稀释法测定紫杉醇(paclitaxel,PTX)单药、PTX+抗菌药联合用药对大肠杆菌(Escherichia coli,E.coli)和金黄色葡萄球菌(Staphylococcus aureus,S.aureus)临床分离株的最低抑菌浓度(minimum inhibitory concentration,MIC),然后用棋盘试验测定PTX与黏菌素(colistin,COL)联合用药的部分抑菌浓度指数(FICI),通过建立小鼠腹腔感染模型,以小鼠的存活率和细菌载量来评估2种药联合的体内治疗效果,并进一步通过测定细胞膜通透性和外排泵活性,探究PTX与COL联用后的抑菌增效机制。MIC检测结果显示,PTX单药对E.coli(G5、E25)的MIC均>1024 mg/L,对S.aureus S238的MIC为512 mg/L;PTX分别与10种抗菌药联用后,可显著增强COL对E.coli的抑菌活性(COL MIC值从4 mg/L和8 mg/L降低至1 mg/L)。棋盘试验结果显示,PTX与COL联合用药对E.coli(G5、E25)的FICI值分别为0.31、0.29,表现出协同抑菌作用;对E.coli G21、S.aureus(S237和S238)的FICI值分别为0.51、0.75和0.53,表现出相加作用。在小鼠腹腔感染模型中,与PTX或COL单药组相比,PTX与COL联合组能显著提高小鼠7 d存活率,并且能极显著降低小鼠肝、脾部E.coli的载菌量(P<0.001)。细胞膜通透性和外排泵活性结果显示,与PTX和COL单药相比,PTX与COL联合用药后可显著增加E.coli(G5和E25)的内膜和外膜的通透性,并且可显著抑制菌株的外排泵活性(P<0.01)。结果表明,PTX与COL联合用药后可通过增加细菌胞膜通透性和抑制外排泵活性而对COL耐药E.coli产生协同体内外抑菌增效作用。本试验为开发新型联合用药方案防控多重耐药性(multi-drug resistance,MDR)E.coli感染提供了理论依据。To explore the in vitro and in vivo synergistic effect of paclitaxel in combination with colistin against MDREscherichia coli(E.coli)and the corresponding mechanism of synergism,we measured the MICs of PTX alone and combination of PTX+antimicrobial drugs on E.coli and Staph ylococcus aureus(S.aureus)by broth microdilution method.Then,checkerboard method was used to determine the FICI of PTX+COL combination,and the antibacterial synergies of PTX and COL was further explored through analyzing the membrane permeability and efflux pump activity.The MICs results showed that the MIC values of PTX alone against E.coli(G5,E25)and S.aureus S238 were>1024 mg/L and 512 mg/L,respectively.Meanwhile,we found that the antibacterial activity of COL against E.coli could be significantly enhanced(MIC decreased by 4 to 8times)when used in combination with PTX.The checkerboard test showed that the FICI values of PTX combined with COL for E.coli(G5,E25)were 0.31 and 0.29,respectively,indicating a synergistic antibacterial effect on these strains.The FICI values of PTX combined with COL for E.coli G21,S.aureus(S237 and S238)were 0.51,0.75 and 0.53,respectively,indicating additive effects on these strains,In the mouse abdominal infection model,the combination group could extremely significantly reduce the bacterial burden of E.coli in abdominal compared to the COL or PTX alone group(P<0.001).The analysis of membrane permeability and efflux pump activity showed that PTX combined with COL significantly increased the inner and outer membrane permeability of E.coli(G5 and E25),and markedly inhibited the efflux pumping activity of E.coli,when compared that of PTX and COL alone(P<0.01).The above results indicated that the combination of PTX and COL could exert a synergistic in vivo and in vitro antibacterial effect on COL-resistant E.coli through increasing bacterial membrane permeability and inhibiting efflux pump activity.This study provides the theoretical foundation for the development of a novel combination regimen for the treatment of

关 键 词：紫杉醇 黏菌素 联合用药 大肠杆菌 抑菌增效 

分 类 号：S852.61[农业科学—基础兽医学] S859.7[农业科学—兽医学]