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

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• 作者：Yi-Yun Liu ; BS^a ; ^&dagger ; ; Yang Wang ; PhD^b ; ^&dagger ; ; Prof Timothy R Walsh ; DSc^c ; Ling-Xian Yi ; BS^a ; Rong Zhang ; PhD^d ; James Spencer ; PhD^e ; Yohei Doi ; MD^f ; Guobao Tian ; PhD^g ; Baolei Dong ; BS^b ; Xianhui Huang ; PhD^a ; Lin-Feng Yu ; BS^a ; Danxia Gu ; PhD^d ; Hongwei Ren ; BS^b ; Xiaojie Chen ; MS^a ; Luchao Lv ; MS^a ; Dandan He ; MS^a ; Hongwei Zhou ; PhD^d ; Prof Zisen Liang ; MS^a ; Prof Jian-Hua Liu ; PhD^a ; ^{jhliu@scau.edu.cn" class="auth_mail" title="E-mail the corresponding author} ; Prof Jianzhong Shen ; PhD^b ; ^{sjz@cau.edu.cn" class="auth_mail" title="E-mail the corresponding author}
• 刊名：The Lancet Infectious Diseases
• 出版年：2016
• 出版时间：February 2016
• 年：2016
• 卷：16
• 期：2
• 页码：161-168
• 全文大小：1434 K

文摘

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.

Findings

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.

Interpretation

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.

Funding

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