Resistance to the antimicrobial peptide polymyxin requires myristoylation of Escherichia coli and Salmonella typhimurium lipid A

An X. Tran, Melissa E. Lester, Christopher M. Stead, Christian R.H. Raetz, Duncan J. Maskell, Sara C. McGrath, Robert J. Cotter, M. Stephen Trent

Research output: Contribution to journalArticlepeer-review

Abstract

Attachment of positively charged, amine-containing residues such as 4-amino-4-deoxy-L-arabinose (L-Ara4N) and phosphoethanolamine (pEtN) to Escherichia coli and Salmonella typhimurium lipid A is required for resistance to the cationic antimicrobial peptide, polymyxin. In an attempt to discover additional lipid A modifications important for polymyxin resistance, we generated polymyxin-sensitive mutants of an E. coli pmrAC strain, WD101. A subset of polymyxin-sensitive mutants produced a lipid A that lacked both the 3′-acyloxyacyl-linked myristate (C14) and L-Ara4N, even though the necessary enzymatic machinery required to synthesize L-Ara4N-modified lipid A was present. Inactivation of lpxM in both E. coli and S. typhimurium resulted in the loss of L-Ara4N addition, as well as, increased sensitivity to polymyxin. However, decoration of the lipid A phosphate groups with pEtN residues was not effected in lpxM mutants. In summary, we demonstrate that attachment of L-Ara4N to the phosphate groups of lipid A and the subsequent resistance to polymyxin is dependent upon the presence of the secondary linked myristoyl group.

Original languageEnglish (US)
Pages (from-to)28186-28194
Number of pages9
JournalJournal of Biological Chemistry
Volume280
Issue number31
DOIs
StatePublished - Aug 5 2005

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Biology
  • Cell Biology

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