Structural modification of lipopolysaccharide conferred by mcr-1 in gram-negative ESKAPE pathogens

Yi Yun Liu, Courtney E. Chandler, Lisa M. Leung, Christi L. McElheny, Roberta T. Mettus, Robert M.Q. Shanks, Jian Hua Liu, David R. Goodlett, Robert K. Ernst, Yohei Doi

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Abstract

mcr-1 was initially reported as the first plasmid-mediated colistin resistance gene in clinical isolates of Escherichia coli and Klebsiella pneumoniae in China and has subsequently been identified worldwide in various species of the family Enterobacteriaceae. mcr-1 encodes a phosphoethanolamine transferase, and its expression has been shown to generate phosphoethanolamine-modified bis-phosphorylated hexa-Acylated lipid A in E. coli. Here, we investigated the effects of mcr-1 on 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, and Enterobacter species) pathogens, which are often treated clinically by colistin. The effects of mcr-1 on colistin resistance were determined using MIC assays of laboratory and clinical strains of E. coli, K. pneumoniae, A. baumannii, and P. aeruginosa. Lipid A structural changes resulting from MCR-1 were analyzed by mass spectrometry. The introduction of mcr-1 led to colistin resistance in E. coli, K. pneumoniae, and A. baumannii but only moderately reduced susceptibility in P. aeruginosa. Phosphoethanolamine modification of lipid A was observed consistently for all four species. These findings highlight the risk of colistin resistance as a consequence of mcr-1 expression among ESKAPE pathogens, especially in K. pneumoniae and A. baumannii. Furthermore, 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 of mcr-1 or plasmidmediated phosphoethanolamine transferases in general.

Original languageEnglish
Article numbere00580-17
JournalAntimicrobial agents and chemotherapy
Volume61
Issue number6
DOIs
Publication statusPublished - 06-2017
Externally publishedYes

All Science Journal Classification (ASJC) codes

  • Pharmacology
  • Pharmacology (medical)
  • Infectious Diseases

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    Liu, Y. Y., Chandler, C. E., Leung, L. M., McElheny, C. L., Mettus, R. T., Shanks, R. M. Q., Liu, J. H., Goodlett, D. R., Ernst, R. K., & Doi, Y. (2017). Structural modification of lipopolysaccharide conferred by mcr-1 in gram-negative ESKAPE pathogens. Antimicrobial agents and chemotherapy, 61(6), [e00580-17]. https://doi.org/10.1128/AAC.00580-17