应对可转移多黏菌素耐药性--饲料添加剂来源的白屈菜红碱具有双重效应  

Dual Effects of Feed-Additive-Derived Chelerythrine in Combating Mobile Colistin Resistance

作　　者：Huangwei Song Xueyang Wang Muchen Zhang Zhiyu Zou Siyuan Yang Tian Yi Jianfeng Wang Dejun Liu Yingbo Shen Chongshan Dai Zhihai Liu Timothy R.Walsh Jianzhong Shen Congming Wu Yang Wang 

机构地区：[1]National Key Laboratory of Veterinary Public Health and Safety,College ofVeterinary Medicine,China Agricultural University,Beijing 100193,China [2]Guangdong Laboratory for Lingnan Modern Agriculture,Guangzhou 510642,China [3]State Key Laboratory for Zoonotic Diseases,Key Laboratory of Zoonosis Research,Ministry of Education,Institute of Zoonosis,College of Veterinary Medicine,Jilin University,Changchun 130015,China [4]College of Chemistry and Pharmaceutical Sciences,Qingdao Agricultural University.Qingdao 266109,China [5]Ineos-Oxford Institute of Antimicrobial Research,Department of Biology,University of Oxford,Oxford OX13SZ,UK

出　　处：《Engineering》2024年第1期163-173,共11页工程（英文）

基　　金：grants from the Laboratory of Lingnan Modern Agriculture Project(NT2021006 to Yang Wang and Jianzhong Shen);the National Natural Science Foundation of China(81861138051 and 81991535 to Yang Wang and Congming Wu).

摘　　要：The emergence and spread of the mobile colistin-resistance gene,mcr-1,and its variants pose achallenge to the use of colistin,a last-resort antibiotic used to treat severe infections caused by extensively drug-resistant(XDR)Gram-negative pathogens.Antibiotic adjuvants are a promising strategy to enhance the efficacy of colistin against colistin-resistant pathogens;however,few studies have considered the effects of adjuvants on limiting resistance-gene transmission.We found that chelerythrine(4 mg·L^(-1))derived from Macleaya cordata extract,which is used as an animal feed additive,reduced the minimal inhibitory concentration(MIC)of colistin against an mcr-1 positive Escherichia coli(E.coli)strain by 16-fold(from 2.000 to 0.125 mg·L^(-1)).eliminated approximately 10^(4) colony-forming units(CFUs)of an mcr-1-carrying strain in a murine intestinal infection model,and inhibited the conjugation of an mcr-1-bearing plasmid in vitro(by>100-fold)and in a mouse model(by up to 5-fold).A detailed analysis revealed that chelery-thrine binds to phospholipids on bacterial membranes and increases cytoplasmic membrane fluidity,thereby impairing respiration,disrupting proton motive force(PMF),generating reactive oxygen species(ROS),and decreasing intracellular adenosine triphosphate(ATP)levels,which subsequently downregu-lates mcr-1 and conjugation-associated genes.These dual effects of chelerythrine can expand the use of antibiotic adjuvants and may provide a new strategy for circumventing mobile colistin resistance.

关 键 词：CHELERYTHRINE Antibiotic adjuvant Conjugation inhibitor COLISTIN mcr-1 Dual effects 

分 类 号：R28[医药卫生—中药学]