Abstract

The continuous increase in the isolation of bacterial pathogens exhibiting resistance to multiple antibiotics has created an urgent need for new therapeutic agents. Natural host-defense peptides and peptide fragments from antibacterial proteins of phagocytic host cells are currently being developed as antimicrobial agents. The pmrA locus of Salmonella typhimurium encodes a two-component regulatory system -PmrA/PmrB - that governs resistance to polymyxin B and antibacterial peptides/proteins of human neutrophils. Polymyxin B-resistant mutants have chemical modifications in the lipopolysaccharide (LPS) that make them less anionic, resulting in decreased binding of polymyxin B and cationic peptides/proteins of PMNs. Experiments are proposed to characterize in molecular detail the PmrA-activated genes which are required for polymyxin B-resistance and to examine the structure of the LPS in mutants defective in PmrA-regulated genes. The mechanism by which pH and divalent cation concentration modulate resistance will be examined by analyzing the interactions between the PhoP/PhoQ and the PmrA/PmrB two-component regulatory systems. The results from these studies should provide a detailed molecular picture for the capacity of Salmonella to resist cationic antibacterial peptides. Moreover, it may also lead to novel strategies to prevent expression of determinants that mediate resistance to antibacterial peptides, thereby allowing the host to clear bacterial infections.

  Funding Agency

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Project (R01)
Project #
5R01AI042236-03
Application #
6149867
Study Section
Bacteriology and Mycology Subcommittee 2 (BM)
Project Start
1998-02-01
Project End
2003-01-31
Budget Start
2000-02-01
Budget End
2001-01-31
Support Year
3
Fiscal Year
2000
Total Cost
$184,863
Indirect Cost

  Institution

Name
Washington University
Department
Microbiology/Immun/Virology
Type
Schools of Medicine
DUNS #
062761671
City
Saint Louis
State
MO
Country
United States
Zip Code
63130

  Publications

May, John F; Groisman, Eduardo A (2013) Conflicting roles for a cell surface modification in Salmonella. Mol Microbiol 88:970-83
Townsend 2nd, Guy E; Raghavan, Varsha; Zwir, Igor et al. (2013) Intramolecular arrangement of sensor and regulator overcomes relaxed specificity in hybrid two-component systems. Proc Natl Acad Sci U S A 110:E161-9
Choi, Jeongjoon; Groisman, Eduardo A (2013) The lipopolysaccharide modification regulator PmrA limits Salmonella virulence by repressing the type three-secretion system Spi/Ssa. Proc Natl Acad Sci U S A 110:9499-504
Groisman, Eduardo A; Hollands, Kerry; Kriner, Michelle A et al. (2013) Bacterial Mg2+ homeostasis, transport, and virulence. Annu Rev Genet 47:625-46
Kato, Akinori; Chen, H Deborah; Latifi, Tammy et al. (2012) Reciprocal control between a bacterium's regulatory system and the modification status of its lipopolysaccharide. Mol Cell 47:897-908
Yeo, Won-Sik; Zwir, Igor; Huang, Henry V et al. (2012) Intrinsic negative feedback governs activation surge in two-component regulatory systems. Mol Cell 45:409-21
Chen, H Deborah; Jewett, Mollie W; Groisman, Eduardo A (2012) An allele of an ancestral transcription factor dependent on a horizontally acquired gene product. PLoS Genet 8:e1003060
Jarvik, Tyler; Smillie, Chris; Groisman, Eduardo A et al. (2010) Short-term signatures of evolutionary change in the Salmonella enterica serovar typhimurium 14028 genome. J Bacteriol 192:560-7
Mitrophanov, Alexander Y; Groisman, Eduardo A (2010) Response acceleration in post-translationally regulated genetic circuits. J Mol Biol 396:1398-409
Raghavan, Varsha; Groisman, Eduardo A (2010) Orphan and hybrid two-component system proteins in health and disease. Curr Opin Microbiol 13:226-31

Showing the most recent 10 out of 22 publications