Mechanisms of Polymyxin Resistance

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Abstract

Polymyxin antibiotics are increasingly being used as last-line therapeutic options against a number of multidrug resistant bacteria. These antibiotics show strong bactericidal activity against a range of Gram-negative bacteria, but with the increased use of these antibiotics resistant strains are emerging at an alarming rate. Furthermore, some Gram-negative species, such as Neisseria meningitidis, Proteus mirabilis and Burkholderia spp., are intrinsically resistant to the action of polymyxins. Most identified polymyxin resistance mechanisms in Gram-negative bacteria involve changes to the lipopolysaccharide (LPS) structure, as polymyxins initially interact with the negatively charged lipid A component of LPS. The controlled addition of positively charged residues such as 4-amino-L-arabinose, phosphoethanolamine and/or galactosamine to LPS results in a reduced negative charge on the bacterial surface and therefore reduced interaction between the polymyxin and the LPS. Polymyxin resistant species produce LPS that intrinsically contains one or more of these additions. While the genes necessary for most of these additions are chromosomally encoded, plasmid-borne phosphoethanolamine transferases (mcr-1 to mcr-8) have recently been identified and these plasmids threaten to increase the rate of dissemination of clinically relevant colistin resistance. Uniquely, Acinetobacter baumannii can also become highly resistant to polymyxins via spontaneous mutations in the lipid A biosynthesis genes lpxA, lpxC or lpxD such that they produce no LPS or lipid A. A range of other non-LPS-dependent polymyxin resistance mechanisms has also been identified in bacteria, but these generally result in only low levels of resistance. These include increased anionic capsular polysaccharide production in Klebsiella pneumoniae, expression of efflux systems such as MtrCDE in N. meningitidis, and altered expression of outer membrane proteins in a small number of species.

Original languageEnglish
Title of host publicationPolymyxin Antibiotics
Subtitle of host publicationFrom Laboratory Bench to Bedside
EditorsJian Li, Roger L. Nation, Keith S. Kaye
Place of PublicationSwitzerland
PublisherSpringer
Chapter5
Pages55-71
Number of pages17
ISBN (Electronic)9783030163730
ISBN (Print)9783030163716
DOIs
Publication statusPublished - Jul 2019

Publication series

NameAdvances in Experimental Medicine and Biology
Volume1145
ISSN (Print)0065-2598
ISSN (Electronic)2214-8019

Keywords

  • Lipid A modification
  • Loss of LPS
  • Polymyxin
  • Remodelling of outer membrane
  • Resistance

Cite this

Moffatt, J. H., Harper, M., & Boyce, J. D. (2019). Mechanisms of Polymyxin Resistance. In J. Li, R. L. Nation, & K. S. Kaye (Eds.), Polymyxin Antibiotics: From Laboratory Bench to Bedside (pp. 55-71). (Advances in Experimental Medicine and Biology; Vol. 1145). Switzerland: Springer. https://doi.org/10.1007/978-3-030-16373-0_5