TY - JOUR
T1 - Resistance to the antimicrobial peptide polymyxin requires myristoylation of Escherichia coli and Salmonella typhimurium lipid A
AU - Tran, An X.
AU - Lester, Melissa E.
AU - Stead, Christopher M.
AU - Raetz, Christian R.H.
AU - Maskell, Duncan J.
AU - McGrath, Sara C.
AU - Cotter, Robert J.
AU - Trent, M. Stephen
PY - 2005/8/5
Y1 - 2005/8/5
N2 - 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.
AB - 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.
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U2 - 10.1074/jbc.M505020200
DO - 10.1074/jbc.M505020200
M3 - Article
C2 - 15951433
AN - SCOPUS:23344452474
SN - 0021-9258
VL - 280
SP - 28186
EP - 28194
JO - Journal of Biological Chemistry
JF - Journal of Biological Chemistry
IS - 31
ER -