title: Structural Modification of Lipopolysaccharide Conferred bymcr-1in Gram-Negative ESKAPE Pathogens.
abstract: mcr-1was initially reported as the first plasmid-mediated colistin resistance gene in clinical isolates ofEscherichia coliandKlebsiella pneumoniaein China and has subsequently been identified worldwide in various species of the familyEnterobacteriaceaemcr-1encodes a phosphoethanolamine transferase, and its expression has been shown to generate phosphoethanolamine-modified bis-phosphorylated hexa-acylated lipid A inE. coliHere, we investigated the effects ofmcr-1on colistin susceptibility and on lipopolysaccharide structures in laboratory and clinical strains of the Gram-negative ESKAPE (Enterococcus faecium,Staphylococcus aureus,K. pneumoniae,Acinetobacter baumannii,Pseudomonas aeruginosa, andEnterobacterspecies) pathogens, which are often treated clinically by colistin. The effects ofmcr-1on colistin resistance were determined using MIC assays of laboratory and clinical strains ofE. coli,K. pneumoniae,A. baumannii, andP. aeruginosaLipid A structural changes resulting from MCR-1 were analyzed by mass spectrometry. The introduction ofmcr-1led to colistin resistance inE. coli,K. pneumoniae, andA. baumanniibut only moderately reduced susceptibility inP. aeruginosaPhosphoethanolamine modification of lipid A was observed consistently for all four species. These findings highlight the risk of colistin resistance as a consequence ofmcr-1expression among ESKAPE pathogens, especially inK. pneumoniaeandA. baumanniiFurthermore, the observation that lipid A structures were modified despite only modest increases in colistin MICs in some instances suggests more sophisticated surveillance methods may need to be developed to track the dissemination ofmcr-1or plasmid-mediated phosphoethanolamine transferases in general.
authors.affiliation: Division of Infectious Diseases, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania, USA.|National Risk Assessment Laboratory for Antimicrobial Resistance of Animal Original Bacteria, College of Veterinary Medicine, South China Agricultural University, Guangzhou, China.
authors.forename: Yi-Yun
authors.initials: YY
authors.lastname: Liu
authors.affiliation: Department of Microbial Pathogenesis, School of Dentistry, University of Maryland Baltimore, Baltimore, Maryland, USA.
authors.forename: Courtney E
authors.initials: CE
authors.lastname: Chandler
authors.affiliation: Department of Microbial Pathogenesis, School of Dentistry, University of Maryland Baltimore, Baltimore, Maryland, USA.
authors.forename: Lisa M
authors.initials: LM
authors.lastname: Leung
authors.affiliation: Division of Infectious Diseases, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania, USA.
authors.forename: Christi L
authors.initials: CL
authors.lastname: McElheny
authors.affiliation: Division of Infectious Diseases, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania, USA.
authors.forename: Roberta T
authors.initials: RT
authors.lastname: Mettus
authors.affiliation: Department of Ophthalmology, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania, USA.
authors.forename: Robert M Q
authors.identifier: 0000-0002-7699-5396
authors.initials: RMQ
authors.lastname: Shanks
authors.affiliation: National Risk Assessment Laboratory for Antimicrobial Resistance of Animal Original Bacteria, College of Veterinary Medicine, South China Agricultural University, Guangzhou, China.
authors.forename: Jian-Hua
authors.initials: JH
authors.lastname: Liu
authors.affiliation: Department of Pharmaceutical Sciences, School of Pharmacy, University of Maryland Baltimore, Baltimore, Maryland, USA.
authors.forename: David R
authors.initials: DR
authors.lastname: Goodlett
authors.affiliation: Department of Microbial Pathogenesis, School of Dentistry, University of Maryland Baltimore, Baltimore, Maryland, USA rkernst@umaryland.edu yod4@pitt.edu.
authors.forename: Robert K
authors.initials: RK
authors.lastname: Ernst
authors.affiliation: Division of Infectious Diseases, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania, USA rkernst@umaryland.edu yod4@pitt.edu.
authors.forename: Yohei
authors.initials: Y
authors.lastname: Doi
mesh_terms: D040981:Acinetobacter baumannii / Q000187:drug effects / Q000235:genetics; D000900:Anti-Bacterial Agents / Q000494:pharmacology*; D001426:Bacterial Proteins / Q000235:genetics / Q000378:metabolism; D003091:Colistin / Q000494:pharmacology; D024881:Drug Resistance, Bacterial / Q000235:genetics; D004926:Escherichia coli / Q000187:drug effects / Q000235:genetics; D007711:Klebsiella pneumoniae / Q000187:drug effects / Q000235:genetics; D008070:Lipopolysaccharides / Q000494:pharmacology*; D008826:Microbial Sensitivity Tests; D010957:Plasmids / Q000235:genetics; D011113:Polymyxins / Q000494:pharmacology; D011550:Pseudomonas aeruginosa / Q000187:drug effects / Q000235:genetics; D013211:Staphylococcus aureus / Q000187:drug effects / Q000235:genetics
chemical_list: D000900:Anti-Bacterial Agents; D001426:Bacterial Proteins; D008070:Lipopolysaccharides; D011113:Polymyxins; D003091:Colistin
keywords: lipid A; phosphoethanolamine; plasmid; plasmid-mediated resistance; polymyxin resistance; polymyxins