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Journal of Bacteriology, July 2004, p. 4124-4133, Vol. 186, No. 13
0021-9193/04/$08.00+0     DOI: 10.1128/JB.186.13.4124-4133.2004
Copyright © 2004, American Society for Microbiology. All Rights Reserved.

The PmrA-Regulated pmrC Gene Mediates Phosphoethanolamine Modification of Lipid A and Polymyxin Resistance in Salmonella enterica

Hyunwoo Lee,1 Fong-Fu Hsu,2 John Turk,2 and Eduardo A. Groisman1,3*

Howard Hughes Medical Institute,3 Department of Molecular Microbiology,1 Mass Spectrometry Resource, Department of Internal Medicine, Division of Endocrinology, Diabetes, and Metabolism, Washington University School of Medicine, St. Louis, Missouri 631102

Received 26 February 2004/ Accepted 5 April 2004

The PmrA/PmrB regulatory system of Salmonella enterica controls the modification of lipid A with aminoarabinose and phosphoethanolamine. The aminoarabinose modification is required for resistance to the antibiotic polymyxin B, as mutations of the PmrA-activated pbg operon or ugd gene result in strains that lack aminoarabinose in their lipid A molecules and are more susceptible to polymyxin B. Additional PmrA-regulated genes appear to participate in polymyxin B resistance, as pbgP and ugd mutants are not as sensitive to polymyxin B as a pmrA mutant. Moreover, the role that the phosphoethanolamine modification of lipid A plays in the resistance to polymyxin B has remained unknown. Here we address both of these questions by establishing that the PmrA-activated pmrC gene encodes an inner membrane protein that is required for the incorporation of phosphoethanolamine into lipid A and for polymyxin B resistance. The PmrC protein consists of an N-terminal region with five transmembrane domains followed by a large periplasmic region harboring the putative enzymatic domain. A pbgP pmrC double mutant resembled a pmrA mutant both in its lipid A profile and in its susceptibility to polymyxin B, indicating that the PmrA-dependent modification of lipid A with aminoarabinose and phosphoethanolamine is responsible for PmrA-regulated polymyxin B resistance.

* Corresponding author. Mailing address: Department of Molecular Microbiology, Washington University School of Medicine, 660 S. Euclid Ave., Campus Box 8230, St. Louis, MO 63110. Phone: (314) 362-3692. Fax: (314) 747-8228. E-mail: groisman{at}borcim.wustl.edu.

Journal of Bacteriology, July 2004, p. 4124-4133, Vol. 186, No. 13
0021-9193/04/$08.00+0     DOI: 10.1128/JB.186.13.4124-4133.2004
Copyright © 2004, American Society for Microbiology. All Rights Reserved.



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