Yi-Yun Liu1, Yang Wang2, Timothy R Walsh3, Ling-Xian Yi1, Rong Zhang4, James Spencer5, Yohei Doi6, Guobao Tian7, Baolei Dong2, Xianhui Huang1, Lin-Feng Yu1, Danxia Gu4, Hongwei Ren2, Xiaojie Chen1, Luchao Lv1, Dandan He1, Hongwei Zhou4, Zisen Liang1, Jian-Hua Liu8, Jianzhong Shen9. 1. College of Veterinary Medicine, National Risk Assessment Laboratory for Antimicrobial Resistance of Microorganisms in Animals, South China Agricultural University, Guangzhou, China. 2. Beijing Advanced Innovation Center for Food Nutrition and Human Health, College of Veterinary Medicine, China Agricultural University, Beijing, China. 3. Department of Medical Microbiology and Infectious Disease, Institute of Infection & Immunity, Heath Park Hospital, Cardiff, UK. 4. The Second Affiliated Hospital of Zhejiang University, Zhejiang University, Hangzhou, China. 5. School of Cellular and Molecular Medicine, University of Bristol, Biomedical Sciences Building, Bristol, UK. 6. Division of Infectious Diseases, University of Pittsburgh Medical Center, Pittsburgh, PA, USA. 7. Sun Yat-sen University Zhongshan School of Medicine, Guangzhou, China. 8. 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. 9. 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.
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.
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.
Authors: Johanne Blais; Sara Lopez; Cindy Li; Alexey Ruzin; Srijan Ranjitkar; Charles R Dean; Jennifer A Leeds; Anthony Casarez; Robert L Simmons; Folkert Reck Journal: Antimicrob Agents Chemother Date: 2018-09-24 Impact factor: 5.191
Authors: Dennis Huang; Brenda Yu; John K Diep; Rajnikant Sharma; Michael Dudley; Jussimara Monteiro; Keith S Kaye; Jason M Pogue; Cely Saad Abboud; Gauri G Rao Journal: Antimicrob Agents Chemother Date: 2017-06-27 Impact factor: 5.191