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Infection and Immunity, November 2000, p. 6139-6146, Vol. 68, No. 11
0019-9567/00/$04.00+0
Copyright © 2000, American Society for Microbiology. All rights reserved.

Genetic and Functional Analysis of a PmrA-PmrB-Regulated Locus Necessary for Lipopolysaccharide Modification, Antimicrobial Peptide Resistance, and Oral Virulence of Salmonella enterica Serovar Typhimurium

John S. Gunn,1,* Sara S. Ryan,1 Jennifer C. Van Velkinburgh,1 Robert K. Ernst,2 and Samuel I. Miller2

Department of Microbiology, University of Texas Health Science Center at San Antonio, San Antonio, Texas 78229,1 and Departments of Medicine and Microbiology, University of Washington, Seattle, Washington 981952

Received 8 June 2000/Returned for modification 28 July 2000/Accepted 4 August 2000

The two-component regulatory system PmrA-PmrB confers resistance of Salmonella spp. to cationic antimicrobial peptides (AP) such as polymyxin (PM), bactericidal/permeability-increasing protein, and azurocidin. This resistance occurs by transcriptional activation of two loci termed pmrE and pmrHFIJKLM. Both pmrE and pmrHFIJKLM produce products required for the biosynthesis of lipid A with 4-aminoarabinose (Ara4N). Ara4N addition creates a more positively charged lipopolysaccharide (LPS) and thus reduces cationic AP binding. Experiments were conducted to further analyze the regulation of the pmrHFIJKLM operon and the role of this operon and the surrounding genomic region in LPS modification and antimicrobial peptide resistance. The pmrHFIJKLM genes are cotranscribed and over 3,000-fold regulated by PmrA-PmrB. The pmrHFIJKLM promoter bound PmrA, as determined by gel shift analysis, as did a 40-bp region of the PmrA-PmrB-regulated pmrCAB promoter. Construction of nonpolar mutations in the pmrHFIJKLM genes showed that all except pmrM were necessary for the Ara4N addition to lipid A and PM resistance. The flanking genes of the operon (pmrG and pmrD) were not necessary for PM resistance, but pmrD was shown to be regulated by the PhoP-PhoQ regulatory system. BALB/c mice inoculated with pmrA and pmrHFIJKLM mutant strains demonstrated virulence attenuation when the strains were administered orally but not when they were administered intraperitoneally, indicating that Ara4N addition may be important for resistance to host innate defenses within intestinal tissues.

* Corresponding author. Mailing address: University of Texas Health Science Center at San Antonio, Department of Microbiology, MC 7758, 7703 Floyd Curl Dr., San Antonio, TX 78229-3900. Phone: (210) 567-3973. Fax: (210) 567-3795. E-mail: gunnj{at}uthscsa.edu.

Infection and Immunity, November 2000, p. 6139-6146, Vol. 68, No. 11
0019-9567/00/$04.00+0
Copyright © 2000, American Society for Microbiology. All rights reserved.


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