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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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