title: Dissemination and Mechanism for the MCR-1 Colistin Resistance.
abstract: Polymyxins are the last line of defense against lethal infections caused by multidrug resistant Gram-negative pathogens. Very recently, the use of polymyxins has been greatly challenged by the emergence of the plasmid-borne mobile colistin resistance gene (mcr-1). However, the mechanistic aspects of the MCR-1 colistin resistance are still poorly understood. Here we report the comparative genomics of two new mcr-1-harbouring plasmids isolated from the human gut microbiota, highlighting the diversity in plasmid transfer of the mcr-1 gene. Further genetic dissection delineated that both the trans-membrane region and a substrate-binding motif are required for the MCR-1-mediated colistin resistance. The soluble form of the membrane protein MCR-1 was successfully prepared and verified. Phylogenetic analyses revealed that MCR-1 is highly homologous to its counterpart PEA lipid A transferase in Paenibacili, a known producer of polymyxins. The fact that the plasmid-borne MCR-1 is placed in a subclade neighboring the chromosome-encoded colistin-resistant Neisseria LptA (EptA) potentially implies parallel evolutionary paths for the two genes. In conclusion, our finding provids a first glimpse of mechanism for the MCR-1-mediated colistin resistance.
authors.affiliation: Department of Medical Microbiology and Parasitology, Zhejiang University School of Medicine, Hangzhou, Zhejiang, China.
authors.forename: Rongsui
authors.initials: R
authors.lastname: Gao
authors.affiliation: CAS Key Laboratory of Pathogenic Microbiology and Immunology, Institute of Microbiology, Chinese Academy of Sciences, Beijing, China.
authors.forename: Yongfei
authors.initials: Y
authors.lastname: Hu
authors.affiliation: Department of Medical Microbiology and Parasitology, Zhejiang University School of Medicine, Hangzhou, Zhejiang, China.
authors.forename: Zhencui
authors.initials: Z
authors.lastname: Li
authors.affiliation: National Risk Assessment Laboratory for Antimicrobial Resistance of Animal Original Bacteria, South China Agricultural University, Guangzhou, China.
authors.forename: Jian
authors.initials: J
authors.lastname: Sun
authors.affiliation: Department of Medical Microbiology and Parasitology, Zhejiang University School of Medicine, Hangzhou, Zhejiang, China.
authors.forename: Qingjing
authors.initials: Q
authors.lastname: Wang
authors.affiliation: Department of Medical Microbiology and Parasitology, Zhejiang University School of Medicine, Hangzhou, Zhejiang, China.
authors.forename: Jingxia
authors.initials: J
authors.lastname: Lin
authors.affiliation: Department of Medical Microbiology and Parasitology, Zhejiang University School of Medicine, Hangzhou, Zhejiang, China.
authors.forename: Huiyan
authors.initials: H
authors.lastname: Ye
authors.affiliation: CAS Key Laboratory of Pathogenic Microbiology and Immunology, Institute of Microbiology, Chinese Academy of Sciences, Beijing, China.
authors.forename: Fei
authors.initials: F
authors.lastname: Liu
authors.affiliation: Department of Biochemistry, University of Illinois, Urbana, Illinois, United States of America.
authors.forename: Swaminath
authors.initials: S
authors.lastname: Srinivas
authors.affiliation: Institute of Biophysics, Chinese Academy of Sciences, Beijing, China.
authors.forename: Defeng
authors.initials: D
authors.lastname: Li
authors.affiliation: CAS Key Laboratory of Pathogenic Microbiology and Immunology, Institute of Microbiology, Chinese Academy of Sciences, Beijing, China.
authors.forename: Baoli
authors.initials: B
authors.lastname: Zhu
authors.affiliation: National Risk Assessment Laboratory for Antimicrobial Resistance of Animal Original Bacteria, South China Agricultural University, Guangzhou, China.
authors.forename: Ya-Hong
authors.initials: YH
authors.lastname: Liu
authors.affiliation: Zhongshan School of Medicine, Sun Yat-sen University, Guangzhou, China.
authors.forename: Guo-Bao
authors.initials: GB
authors.lastname: Tian
authors.affiliation: Department of Medical Microbiology and Parasitology, Zhejiang University School of Medicine, Hangzhou, Zhejiang, China.
authors.forename: Youjun
authors.initials: Y
authors.lastname: Feng
mesh_terms: D001483:Base Sequence; D003091:Colistin / Q000494:pharmacology*; D024881:Drug Resistance, Bacterial / Q000187:drug effects / Q000235:genetics*; D018432:Drug Resistance, Multiple / Q000502:physiology; D029968:Escherichia coli Proteins / Q000235:genetics*; D006801:Humans; D008826:Microbial Sensitivity Tests; D010802:Phylogeny; D010957:Plasmids
chemical_list: D029968:Escherichia coli Proteins; C000614037:MCR-1 protein, E coli; D003091:Colistin