title: Emergence of plasmid-mediated colistin resistance mechanism MCR-1 in animals and human beings in China: a microbiological and molecular biological study.
abstract: BACKGROUND
  Until now, polymyxin resistance has involved chromosomal mutations but has never been reported via horizontal gene transfer. During a routine surveillance project on antimicrobial resistance in commensal Escherichia coli from food animals in China, a major increase of colistin resistance was observed. When an E coli strain, SHP45, possessing colistin resistance that could be transferred to another strain, was isolated from a pig, we conducted further analysis of possible plasmid-mediated polymyxin resistance. Herein, we report the emergence of the first plasmid-mediated polymyxin resistance mechanism, MCR-1, in Enterobacteriaceae.
  
  
  METHODS
  The mcr-1 gene in E coli strain SHP45 was identified by whole plasmid sequencing and subcloning. MCR-1 mechanistic studies were done with sequence comparisons, homology modelling, and electrospray ionisation mass spectrometry. The prevalence of mcr-1 was investigated in E coli and Klebsiella pneumoniae strains collected from five provinces between April, 2011, and November, 2014. The ability of MCR-1 to confer polymyxin resistance in vivo was examined in a murine thigh model.
  
  
  RESULTS
  Polymyxin resistance was shown to be singularly due to the plasmid-mediated mcr-1 gene. The plasmid carrying mcr-1 was mobilised to an E coli recipient at a frequency of 10(-1) to 10(-3) cells per recipient cell by conjugation, and maintained in K pneumoniae and Pseudomonas aeruginosa. In an in-vivo model, production of MCR-1 negated the efficacy of colistin. MCR-1 is a member of the phosphoethanolamine transferase enzyme family, with expression in E coli resulting in the addition of phosphoethanolamine to lipid A. We observed mcr-1 carriage in E coli isolates collected from 78 (15%) of 523 samples of raw meat and 166 (21%) of 804 animals during 2011-14, and 16 (1%) of 1322 samples from inpatients with infection.
  
  
  CONCLUSIONS
  The emergence of MCR-1 heralds the breach of the last group of antibiotics, polymyxins, by plasmid-mediated resistance. Although currently confined to China, MCR-1 is likely to emulate other global resistance mechanisms such as NDM-1. Our findings emphasise the urgent need for coordinated global action in the fight against pan-drug-resistant Gram-negative bacteria.
  
  
  BACKGROUND
  Ministry of Science and Technology of China, National Natural Science Foundation of China.
authors.affiliation: College of Veterinary Medicine, National Risk Assessment Laboratory for Antimicrobial Resistance of Microorganisms in Animals, South China Agricultural University, Guangzhou, China.
authors.forename: Yi-Yun
authors.initials: YY
authors.lastname: Liu
authors.affiliation: Beijing Advanced Innovation Center for Food Nutrition and Human Health, College of Veterinary Medicine, China Agricultural University, Beijing, China.
authors.forename: Yang
authors.initials: Y
authors.lastname: Wang
authors.affiliation: Department of Medical Microbiology and Infectious Disease, Institute of Infection & Immunity, Heath Park Hospital, Cardiff, UK.
authors.forename: Timothy R
authors.initials: TR
authors.lastname: Walsh
authors.affiliation: College of Veterinary Medicine, National Risk Assessment Laboratory for Antimicrobial Resistance of Microorganisms in Animals, South China Agricultural University, Guangzhou, China.
authors.forename: Ling-Xian
authors.initials: LX
authors.lastname: Yi
authors.affiliation: The Second Affiliated Hospital of Zhejiang University, Zhejiang University, Hangzhou, China.
authors.forename: Rong
authors.initials: R
authors.lastname: Zhang
authors.affiliation: School of Cellular and Molecular Medicine, University of Bristol, Biomedical Sciences Building, Bristol, UK.
authors.forename: James
authors.initials: J
authors.lastname: Spencer
authors.affiliation: Division of Infectious Diseases, University of Pittsburgh Medical Center, Pittsburgh, PA, USA.
authors.forename: Yohei
authors.initials: Y
authors.lastname: Doi
authors.affiliation: Sun Yat-sen University Zhongshan School of Medicine, Guangzhou, China.
authors.forename: Guobao
authors.initials: G
authors.lastname: Tian
authors.affiliation: Beijing Advanced Innovation Center for Food Nutrition and Human Health, College of Veterinary Medicine, China Agricultural University, Beijing, China.
authors.forename: Baolei
authors.initials: B
authors.lastname: Dong
authors.affiliation: College of Veterinary Medicine, National Risk Assessment Laboratory for Antimicrobial Resistance of Microorganisms in Animals, South China Agricultural University, Guangzhou, China.
authors.forename: Xianhui
authors.initials: X
authors.lastname: Huang
authors.affiliation: College of Veterinary Medicine, National Risk Assessment Laboratory for Antimicrobial Resistance of Microorganisms in Animals, South China Agricultural University, Guangzhou, China.
authors.forename: Lin-Feng
authors.initials: LF
authors.lastname: Yu
authors.affiliation: The Second Affiliated Hospital of Zhejiang University, Zhejiang University, Hangzhou, China.
authors.forename: Danxia
authors.initials: D
authors.lastname: Gu
authors.affiliation: Beijing Advanced Innovation Center for Food Nutrition and Human Health, College of Veterinary Medicine, China Agricultural University, Beijing, China.
authors.forename: Hongwei
authors.initials: H
authors.lastname: Ren
authors.affiliation: College of Veterinary Medicine, National Risk Assessment Laboratory for Antimicrobial Resistance of Microorganisms in Animals, South China Agricultural University, Guangzhou, China.
authors.forename: Xiaojie
authors.initials: X
authors.lastname: Chen
authors.affiliation: College of Veterinary Medicine, National Risk Assessment Laboratory for Antimicrobial Resistance of Microorganisms in Animals, South China Agricultural University, Guangzhou, China.
authors.forename: Luchao
authors.initials: L
authors.lastname: Lv
authors.affiliation: College of Veterinary Medicine, National Risk Assessment Laboratory for Antimicrobial Resistance of Microorganisms in Animals, South China Agricultural University, Guangzhou, China.
authors.forename: Dandan
authors.initials: D
authors.lastname: He
authors.affiliation: The Second Affiliated Hospital of Zhejiang University, Zhejiang University, Hangzhou, China.
authors.forename: Hongwei
authors.initials: H
authors.lastname: Zhou
authors.affiliation: College of Veterinary Medicine, National Risk Assessment Laboratory for Antimicrobial Resistance of Microorganisms in Animals, South China Agricultural University, Guangzhou, China.
authors.forename: Zisen
authors.initials: Z
authors.lastname: Liang
authors.affiliation: College of Veterinary Medicine, National Risk Assessment Laboratory for Antimicrobial Resistance of Microorganisms in Animals, South China Agricultural University, Guangzhou, China. Electronic address: jhliu@scau.edu.cn.
authors.forename: Jian-Hua
authors.initials: JH
authors.lastname: Liu
authors.affiliation: Beijing Advanced Innovation Center for Food Nutrition and Human Health, College of Veterinary Medicine, China Agricultural University, Beijing, China. Electronic address: sjz@cau.edu.cn.
authors.forename: Jianzhong
authors.initials: J
authors.lastname: Shen
mesh_terms: D000818:Animals; D002681:China; D003091:Colistin / Q000627:therapeutic use*; D024881:Drug Resistance, Bacterial / Q000276:immunology; D004755:Enterobacteriaceae / Q000187:drug effects*; D004756:Enterobacteriaceae Infections / Q000188:drug therapy* / Q000276:immunology*; D006801:Humans; D008460:Meat / Q000382:microbiology; D051379:Mice; D010957:Plasmids / Q000276:immunology*; D011113:Polymyxins / Q000627:therapeutic use*; D013552:Swine; D013553:Swine Diseases / Q000188:drug therapy*
chemical_list: D011113:Polymyxins; D003091:Colistin