Emergence of plasmid-mediated colistin resistance mechanism MCR-1 in animals and human beings in China: a microbiological and molecular biological study

• Published in: The Lancet infectious diseases Vol. 16; no. 2; pp. 161 - 168
• Main Authors: Liu, Yi-Yun, Wang, Yang, Walsh, Timothy R, Yi, Ling-Xian, Zhang, Rong, Spencer, James, Doi, Yohei, Tian, Guobao, Dong, Baolei, Huang, Xianhui, Yu, Lin-Feng, Gu, Danxia, Ren, Hongwei, Chen, Xiaojie, Lv, Luchao, He, Dandan, Zhou, Hongwei, Liang, Zisen, Liu, Jian-Hua, Shen, Jianzhong
• Format: Journal Article
• Language: English
• Published: United States Elsevier Ltd 01.02.2016; Elsevier Limited
• Subjects: Agriculture; Animals; Antibiotics; Antimicrobial agents; Bacteria; Bacteriology; China; Colistin - therapeutic use; Drug resistance; Drug Resistance, Bacterial - immunology; E coli; Enterobacteriaceae; Enterobacteriaceae - drug effects; Enterobacteriaceae Infections - drug therapy; Enterobacteriaceae Infections - immunology; Escherichia coli; Farms; Food; Gram-negative bacteria; Hogs; Humans; Infectious Disease; Infectious diseases; Klebsiella pneumoniae; Laboratory animals; Lipids; Mass spectrometry; Meat - microbiology; Mice; Plasmids - immunology; Polymyxins - therapeutic use; Pseudomonas aeruginosa; Surveillance; Swine; Swine Diseases - drug therapy; Veterinary medicine; China
• ISSN: 1473-3099; 1474-4457; 1474-4457
• DOI: 10.1016/S1473-3099(15)00424-7

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. 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. 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. 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. Ministry of Science and Technology of China, National Natural Science Foundation of China.