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J. Biol. Chem., Vol. 280, Issue 31, 28186-28194, August 5, 2005

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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**, and M. Stephen Trent

From the Department of Microbiology, J. H. Quillen College of Medicine, Johnson City, Tennessee 37614, the ^¶Department of Biochemistry, Duke University Medical Center, Durham, North Carolina 27710, the ^||Department of Veterinary Medicine, Centre for Veterinary Science, University of Cambridge, Cambridge CB3 OES, United Kingdom, and the ^**Department of Pharmacology and Molecular Sciences, Johns Hopkins University School of Medicine, Baltimore, Maryland 21205

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 pmrA^C 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.

Received for publication, May 5, 2005 , and in revised form, June 8, 2005.

^* The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

These authors contributed equally to this work.

To whom correspondence should be addressed: J. H. Quillen College of Medicine, Box 70579, Johnson City, TN 37614. Tel.: 423-439-6293; Fax: 423-439-8044; E-mail: trentms{at}mail.etsu.edu.

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