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Emergence of plasmid-mediated colistin resistance mechanism MCR-1 in animals and human beings in China: a microbiological and molecular biological study.
Lancet Infect Dis. 2016 Feb; 16(2):161-8.LI

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.

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.

Links

Publisher Full Text (DOI)

Authors+Show Affiliations

Liu YY
College of Veterinary Medicine, National Risk Assessment Laboratory for Antimicrobial Resistance of Microorganisms in Animals, South China Agricultural University, Guangzhou, China.
Wang Y
Beijing Advanced Innovation Center for Food Nutrition and Human Health, College of Veterinary Medicine, China Agricultural University, Beijing, China.
Walsh TR
Department of Medical Microbiology and Infectious Disease, Institute of Infection & Immunity, Heath Park Hospital, Cardiff, UK.
Yi LX
College of Veterinary Medicine, National Risk Assessment Laboratory for Antimicrobial Resistance of Microorganisms in Animals, South China Agricultural University, Guangzhou, China.
Zhang R
The Second Affiliated Hospital of Zhejiang University, Zhejiang University, Hangzhou, China.
Spencer J
School of Cellular and Molecular Medicine, University of Bristol, Biomedical Sciences Building, Bristol, UK.
Doi Y
Division of Infectious Diseases, University of Pittsburgh Medical Center, Pittsburgh, PA, USA.
Tian G
Sun Yat-sen University Zhongshan School of Medicine, Guangzhou, China.
Dong B
Beijing Advanced Innovation Center for Food Nutrition and Human Health, College of Veterinary Medicine, China Agricultural University, Beijing, China.
Huang X
College of Veterinary Medicine, National Risk Assessment Laboratory for Antimicrobial Resistance of Microorganisms in Animals, South China Agricultural University, Guangzhou, China.
Yu LF
College of Veterinary Medicine, National Risk Assessment Laboratory for Antimicrobial Resistance of Microorganisms in Animals, South China Agricultural University, Guangzhou, China.
Gu D
The Second Affiliated Hospital of Zhejiang University, Zhejiang University, Hangzhou, China.
Ren H
Beijing Advanced Innovation Center for Food Nutrition and Human Health, College of Veterinary Medicine, China Agricultural University, Beijing, China.
Chen X
College of Veterinary Medicine, National Risk Assessment Laboratory for Antimicrobial Resistance of Microorganisms in Animals, South China Agricultural University, Guangzhou, China.
Lv L
College of Veterinary Medicine, National Risk Assessment Laboratory for Antimicrobial Resistance of Microorganisms in Animals, South China Agricultural University, Guangzhou, China.
He D
College of Veterinary Medicine, National Risk Assessment Laboratory for Antimicrobial Resistance of Microorganisms in Animals, South China Agricultural University, Guangzhou, China.
Zhou H
The Second Affiliated Hospital of Zhejiang University, Zhejiang University, Hangzhou, China.
Liang Z
College of Veterinary Medicine, National Risk Assessment Laboratory for Antimicrobial Resistance of Microorganisms in Animals, South China Agricultural University, Guangzhou, China.
Liu JH
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.
Shen J
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.

MeSH

AnimalsChinaColistinDrug Resistance, BacterialEnterobacteriaceaeEnterobacteriaceae InfectionsHumansMeatMicePlasmidsPolymyxinsSwineSwine Diseases

Pub Type(s)

Journal Article
Research Support, Non-U.S. Gov't

Language

eng

PubMed ID

26603172

Citation

Liu, Yi-Yun, et al. "Emergence of Plasmid-mediated Colistin Resistance Mechanism MCR-1 in Animals and Human Beings in China: a Microbiological and Molecular Biological Study." The Lancet. Infectious Diseases, vol. 16, no. 2, 2016, pp. 161-8.
Liu YY, Wang Y, Walsh TR, et al. Emergence of plasmid-mediated colistin resistance mechanism MCR-1 in animals and human beings in China: a microbiological and molecular biological study. Lancet Infect Dis. 2016;16(2):161-8.
Liu, Y. Y., Wang, Y., Walsh, T. R., Yi, L. X., Zhang, R., Spencer, J., Doi, Y., Tian, G., Dong, B., Huang, X., Yu, L. F., Gu, D., Ren, H., Chen, X., Lv, L., He, D., Zhou, H., Liang, Z., Liu, J. H., & Shen, J. (2016). Emergence of plasmid-mediated colistin resistance mechanism MCR-1 in animals and human beings in China: a microbiological and molecular biological study. The Lancet. Infectious Diseases, 16(2), 161-8. https://doi.org/10.1016/S1473-3099(15)00424-7
Liu YY, et al. Emergence of Plasmid-mediated Colistin Resistance Mechanism MCR-1 in Animals and Human Beings in China: a Microbiological and Molecular Biological Study. Lancet Infect Dis. 2016;16(2):161-8. PubMed PMID: 26603172.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Emergence of plasmid-mediated colistin resistance mechanism MCR-1 in animals and human beings in China: a microbiological and molecular biological study. AU - Liu,Yi-Yun, AU - Wang,Yang, AU - Walsh,Timothy R, AU - Yi,Ling-Xian, AU - Zhang,Rong, AU - Spencer,James, AU - Doi,Yohei, AU - Tian,Guobao, AU - Dong,Baolei, AU - Huang,Xianhui, AU - Yu,Lin-Feng, AU - Gu,Danxia, AU - Ren,Hongwei, AU - Chen,Xiaojie, AU - Lv,Luchao, AU - He,Dandan, AU - Zhou,Hongwei, AU - Liang,Zisen, AU - Liu,Jian-Hua, AU - Shen,Jianzhong, Y1 - 2015/11/19/ PY - 2015/09/21/received PY - 2015/10/28/revised PY - 2015/10/28/accepted PY - 2015/11/26/entrez PY - 2015/11/26/pubmed PY - 2016/7/7/medline SP - 161 EP - 8 JF - The Lancet. Infectious diseases JO - Lancet Infect Dis VL - 16 IS - 2 N2 - 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. 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. SN - 1474-4457 UR - https://www.unboundmedicine.com/medline/citation/26603172/full_citation DB - PRIME DP - Unbound Medicine ER -