Structural Modification of Lipopolysaccharide Conferred by mcr-1 in Gram-Negative ESKAPE Pathogens

Abstract

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

Small molecule adjuvants that suppress both chromosomal and mcr-1 encoded colistin-resistance and amplify colistin efficacy in polymyxin-susceptible bacteria

“…10 The MICs of colistin against both the parent and transfected strains are summarized in Table 1. Briefly, bacteria were cultured in cation-adjusted Mueller-Hinton broth (CAMHB) for approx.…”

“…As mcr-1 encodes a phosphoethanolamine transferase (PEtN)) that modifies lipid A 10 we studied the extent of lipid A modification post treatment with compound 2 . As a test strain, A. baumannii ATCC 17978 +mcr-1 was grown in the presence or absence of 30 μM compound 2 for 24 hours, at which point lipid A was isolated and analyzed.…”

mcr-1 facilitated selection of high-level colistin-resistant mutants in Escherichia coli

“…The typical modification was the addition of cationic phosphoethanolamine (pEtN) and/or 4-amino-4-deoxy-L-arabinose (L-Ara4N) moieties to phosphate groups on the lipid A component of LPS [1,6,7]. The mcr-1 gene also modifies LPS by encoding a pEtN transferase and mediating addition of pEtN to lipid A [4,8,9]_ENREF_10.…”

Old drug, new findings: colistin resistance and dependence of Acinetobacter baumannii

“…isolates [60]. However, a mcr-1-carrying plasmid could be introduced into A. baumannii, and reduced susceptibility to colistin was observed, highlighting the risk of horizontal transfer of colistin resistance in A. baumannii [61].…”