This Article Full Text (PDF) Alert me when this article is cited Alert me if a correction is posted Services Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Reprints and Permissions Copyright Information Books from ASM Press MicrobeWorld Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Groisman, E. A. Articles by Soncini, F. C. Search for Related Content PubMed PubMed Citation Articles by Groisman, E. A. Articles by Soncini, F. C.

 Previous Article  |  Next Article 

J. Bacteriol., Nov 1997, 7040-7045, Vol 179, No. 22
Copyright © 1997, American Society for Microbiology

Regulation of polymyxin resistance and adaptation to low-Mg2+ environments

EA Groisman, J Kayser and FC Soncini
Howard Hughes Medical Institute and Department of Molecular Microbiology, Washington University School of Medicine, St. Louis, Missouri 63110, USA. groisman@borcim.wustl.edu

The PmrA-PmrB two-component system of Salmonella typhimurium controls resistance to the peptide antibiotic polymyxin B and to several antimicrobial proteins from human neutrophils. Amino acid substitutions in the regulatory protein PmrA conferring resistance to polymyxin lower the overall negative charge of the lipopolysaccharide (LPS), which results in decreased bacterial binding to cationic polypeptides and increased bacterial survival within human neutrophils. We have now identified three PmrA-activated loci that are required for polymyxin resistance. These loci were previously shown to be necessary for growth on low-Mg2+ solid media, indicating that LPS modifications that mediate polymyxin resistance are responsible for the adaptation to Mg2+-limited environments. Conditions that promote transcription of PmrA-activated genes--growth in mildly acidic pH and micromolar Mg2+ concentrations-- increased survival in the presence of polymyxin over 16,000-fold in a wild-type organism but not in a mutant lacking pmrA. Our experiments suggest that low pH and low Mg2+ concentrations may induce expression of PmrA-activated genes within phagocytic cells and promote bacterial resistance to host antimicrobial proteins. We propose that the LPS is a Mg2+ reservoir and that the PmrA-controlled LPS modifications neutralize surface negative charges when Mg2+ is transported into the cytoplasm during growth in Mg2+-limited environments.

This article has been cited by other articles:

• Lamarche, M. G., Kim, S.-H., Crepin, S., Mourez, M., Bertrand, N., Bishop, R. E., Dubreuil, J. D., Harel, J. (2008). Modulation of Hexa-Acyl Pyrophosphate Lipid A Population under Escherichia coli Phosphate (Pho) Regulon Activation. J. Bacteriol. 190: 5256-5264 [Abstract] [Full Text]  
• Landman, D., Georgescu, C., Martin, D. A., Quale, J. (2008). Polymyxins Revisited. Clin. Microbiol. Rev. 21: 449-465 [Abstract] [Full Text]  
• Goldman, S. R., Tu, Y., Goldberg, M. B. (2008). Differential Regulation by Magnesium of the Two MsbB Paralogs of Shigella flexneri. J. Bacteriol. 190: 3526-3537 [Abstract] [Full Text]  
• Yan, A., Guan, Z., Raetz, C. R. H. (2007). An Undecaprenyl Phosphate-Aminoarabinose Flippase Required for Polymyxin Resistance in Escherichia coli. J. Biol. Chem. 282: 36077-36089 [Abstract] [Full Text]  
• Murata, T., Tseng, W., Guina, T., Miller, S. I., Nikaido, H. (2007). PhoPQ-Mediated Regulation Produces a More Robust Permeability Barrier in the Outer Membrane of Salmonella enterica Serovar Typhimurium. J. Bacteriol. 189: 7213-7222 [Abstract] [Full Text]  
• Kato, A., Mitrophanov, A. Y., Groisman, E. A. (2007). A connector of two-component regulatory systems promotes signal amplification and persistence of expression. Proc. Natl. Acad. Sci. USA 104: 12063-12068 [Abstract] [Full Text]  
• Ortega, X. P., Cardona, S. T., Brown, A. R., Loutet, S. A., Flannagan, R. S., Campopiano, D. J., Govan, J. R. W., Valvano, M. A. (2007). A Putative Gene Cluster for Aminoarabinose Biosynthesis Is Essential for Burkholderia cenocepacia Viability. J. Bacteriol. 189: 3639-3644 [Abstract] [Full Text]  
• Golubeva, Y. A., Slauch, J. M. (2006). Salmonella enterica Serovar Typhimurium Periplasmic Superoxide Dismutase SodCI Is a Member of the PhoPQ Regulon and Is Induced in Macrophages. J. Bacteriol. 188: 7853-7861 [Abstract] [Full Text]  
• Tu, X., Latifi, T., Bougdour, A., Gottesman, S., Groisman, E. A. (2006). The PhoP/PhoQ two-component system stabilizes the alternative sigma factor RpoS in Salmonella enterica. Proc. Natl. Acad. Sci. USA 103: 13503-13508 [Abstract] [Full Text]  
• Reynolds, C. M., Ribeiro, A. A., McGrath, S. C., Cotter, R. J., Raetz, C. R. H., Trent, M. S. (2006). An Outer Membrane Enzyme Encoded by Salmonella typhimurium lpxR That Removes the 3'-Acyloxyacyl Moiety of Lipid A. J. Biol. Chem. 281: 21974-21987 [Abstract] [Full Text]  
• Trent, M. S., Stead, C. M., Tran, A. X., Hankins, J. V. (2006). Invited review: Diversity of endotoxin and its impact on pathogenesis. Innate Immunity 12: 205-223 [Abstract]  
• Kim, S.-H., Jia, W., Parreira, V. R., Bishop, R. E., Gyles, C. L. (2006). Phosphoethanolamine substitution in the lipid A of Escherichia coli O157 : H7 and its association with PmrC.. Microbiology 152: 657-666 [Abstract] [Full Text]  
• Rebeil, R., Ernst, R. K., Jarrett, C. O., Adams, K. N., Miller, S. I., Hinnebusch, B. J. (2006). Characterization of Late Acyltransferase Genes of Yersinia pestis and Their Role in Temperature-Dependent Lipid A Variation. J. Bacteriol. 188: 1381-1388 [Abstract] [Full Text]  
• Merighi, M., Carroll-Portillo, A., Septer, A. N., Bhatiya, A., Gunn, J. S. (2006). Role of Salmonella enterica Serovar Typhimurium Two-Component System PreA/PreB in Modulating PmrA-Regulated Gene Transcription. J. Bacteriol. 188: 141-149 [Abstract] [Full Text]  
• GROISMAN, E.A., CROMIE, M.J., SHI, Y., LATIFI, T. (2006). A Mg2+-responding RNA That Controls the Expression of a Mg2+ Transporter. Cold Spring Harb Symp Quant Biol 71: 251-258 [Abstract]  
• Martin-Orozco, N., Touret, N., Zaharik, M. L., Park, E., Kopelman, R., Miller, S., Finlay, B. B., Gros, P., Grinstein, S. (2006). Visualization of Vacuolar Acidification-induced Transcription of Genes of Pathogens inside Macrophages. Mol. Biol. Cell 17: 498-510 [Abstract] [Full Text]  
• Brodsky, I. E., Gunn, J. S. (2005). A Bacterial Sensory System that Activates Resistance to Innate Immune Defenses: Potential Targets for Antimicrobial Therapeutics. Mol. Interv. 5: 335-337 [Abstract] [Full Text]  
• Spiers, A. J., Rainey, P. B. (2005). The Pseudomonas fluorescens SBW25 wrinkly spreader biofilm requires attachment factor, cellulose fibre and LPS interactions to maintain strength and integrity. Microbiology 151: 2829-2839 [Abstract] [Full Text]  
• Tzeng, Y.-L., Ambrose, K. D., Zughaier, S., Zhou, X., Miller, Y. K., Shafer, W. M., Stephens, D. S. (2005). Cationic Antimicrobial Peptide Resistance in Neisseria meningitidis. J. Bacteriol. 187: 5387-5396 [Abstract] [Full Text]  
• Frirdich, E., Whitfield, C. (2005). Review: Lipopolysaccharide inner core oligosaccharide structure and outer membrane stability in human pathogens belonging to the Enterobacteriaceae. Innate Immunity 11: 133-144 [Abstract]  
• Tamayo, R., Choudhury, B., Septer, A., Merighi, M., Carlson, R., Gunn, J. S. (2005). Identification of cptA, a PmrA-Regulated Locus Required for Phosphoethanolamine Modification of the Salmonella enterica Serovar Typhimurium Lipopolysaccharide Core. J. Bacteriol. 187: 3391-3399 [Abstract] [Full Text]  
• Winfield, M. D., Latifi, T., Groisman, E. A. (2005). Transcriptional Regulation of the 4-Amino-4-deoxy-L-arabinose Biosynthetic Genes in Yersinia pestis. J. Biol. Chem. 280: 14765-14772 [Abstract] [Full Text]  
• Winfield, M. D., Groisman, E. A. (2004). Phenotypic differences between Salmonella and Escherichia coli resulting from the disparate regulation of homologous genes. Proc. Natl. Acad. Sci. USA 101: 17162-17167 [Abstract] [Full Text]  
• Marceau, M., Sebbane, F., Ewann, F., Collyn, F., Lindner, B., Campos, M. A., Bengoechea, J.-A., Simonet, M. (2004). The pmrF polymyxin-resistance operon of Yersinia pseudotuberculosis is upregulated by the PhoP-PhoQ two-component system but not by PmrA-PmrB, and is not required for virulence. Microbiology 150: 3947-3957 [Abstract] [Full Text]  
• Kato, A., Groisman, E. A. (2004). Connecting two-component regulatory systems by a protein that protects a response regulator from dephosphorylation by its cognate sensor. Genes Dev. 18: 2302-2313 [Abstract] [Full Text]  
• Shi, Y., Latifi, T., Cromie, M. J., Groisman, E. A. (2004). Transcriptional Control of the Antimicrobial Peptide Resistance ugtL Gene by the Salmonella PhoP and SlyA Regulatory Proteins. J. Biol. Chem. 279: 38618-38625 [Abstract] [Full Text]  
• Lee, H., Hsu, F.-F., Turk, J., Groisman, E. A. (2004). The PmrA-Regulated pmrC Gene Mediates Phosphoethanolamine Modification of Lipid A and Polymyxin Resistance in Salmonella enterica. J. Bacteriol. 186: 4124-4133 [Abstract] [Full Text]  
• Breazeale, S. D., Ribeiro, A. A., Raetz, C. R. H. (2003). Origin of Lipid A Species Modified with 4-Amino-4-deoxy-L-arabinose in Polymyxin-resistant Mutants of Escherichia coli: AN AMINOTRANSFERASE (ArnB) THAT GENERATES UDP-4-AMINO-4-DEOXY-L-ARABINOSE. J. Biol. Chem. 278: 24731-24739 [Abstract] [Full Text]  
• Yeaman, M. R., Yount, N. Y. (2003). Mechanisms of Antimicrobial Peptide Action and Resistance. Pharmacol. Rev. 55: 27-55 [Abstract] [Full Text]  
• Tamayo, R., Ryan, S. S., McCoy, A. J., Gunn, J. S. (2002). Identification and Genetic Characterization of PmrA-Regulated Genes and Genes Involved in Polymyxin B Resistance in Salmonella enterica Serovar Typhimurium. Infect. Immun. 70: 6770-6778 [Abstract] [Full Text]  
• Ferguson, G. P., Roop II, R. M., Walker, G. C. (2002). Deficiency of a Sinorhizobium meliloti bacA Mutant in Alfalfa Symbiosis Correlates with Alteration of the Cell Envelope. J. Bacteriol. 184: 5625-5632 [Abstract] [Full Text]  
• Brodsky, I. E., Ernst, R. K., Miller, S. I., Falkow, S. (2002). mig-14 Is a Salmonella Gene That Plays a Role in Bacterial Resistance to Antimicrobial Peptides. J. Bacteriol. 184: 3203-3213 [Abstract] [Full Text]  
• Trent, M. S., Ribeiro, A. A., Doerrler, W. T., Lin, S., Cotter, R. J., Raetz, C. R. H. (2001). Accumulation of a Polyisoprene-linked Amino Sugar in Polymyxin-resistant Salmonella typhimurium and Escherichia coli. STRUCTURAL CHARACTERIZATION AND TRANSFER TO LIPID A IN THE PERIPLASM. J. Biol. Chem. 276: 43132-43144 [Abstract] [Full Text]  
• Groisman, E. A. (2001). The Pleiotropic Two-Component Regulatory System PhoP-PhoQ. J. Bacteriol. 183: 1835-1842 [Full Text]  
• Gronow, S., Brade, H. (2001). Invited review: Lipopolysaccharide biosynthesis: which steps do bacteria need to survive?. Innate Immunity 7: 3-23 [Abstract]  
• Raetz, C. R.H. (2001). Regulated covalent modifications of lipid A. Innate Immunity 7: 73-78 [Abstract]  
• Gales, A. C., Reis, A. O., Jones, R. N. (2001). Contemporary Assessment of Antimicrobial Susceptibility Testing Methods for Polymyxin B and Colistin: Review of Available Interpretative Criteria and Quality Control Guidelines. J. Clin. Microbiol. 39: 183-190 [Abstract] [Full Text]  
• Guina, T., Yi, E. C., Wang, H., Hackett, M., Miller, S. I. (2000). A PhoP-Regulated Outer Membrane Protease of Salmonella enterica Serovar Typhimurium Promotes Resistance to Alpha-Helical Antimicrobial Peptides. J. Bacteriol. 182: 4077-4086 [Abstract] [Full Text]  
• Aguirre, A., Lejona, S., Véscovi, E. G., Soncini, F. C. (2000). Phosphorylated PmrA Interacts with the Promoter Region of ugd in Salmonella enterica Serovar Typhimurium. J. Bacteriol. 182: 3874-3876 [Abstract] [Full Text]  
• Zhou, Z., Ribeiro, A. A., Raetz, C. R. H. (2000). High-resolution NMR Spectroscopy of Lipid A Molecules Containing 4-Amino-4-deoxy-L-arabinose and Phosphoethanolamine Substituents. DIFFERENT ATTACHMENT SITES ON LIPID A MOLECULES FROM NH4VO3-TREATED ESCHERICHIA COLI VERSUS kdsA MUTANTS OF SALMONELLA TYPHIMURIUM. J. Biol. Chem. 275: 13542-13551 [Abstract] [Full Text]  
• Wosten, M. M. S. M., Groisman, E. A. (1999). Molecular Characterization of the PmrA Regulon. J. Biol. Chem. 274: 27185-27190 [Abstract] [Full Text]  
• Hilliard, J. J., Goldschmidt, R. M., Licata, L., Baum, E. Z., Bush, K. (1999). Multiple Mechanisms of Action for Inhibitors of Histidine Protein Kinases from Bacterial Two-Component Systems. Antimicrob. Agents Chemother. 43: 1693-1699 [Abstract] [Full Text]  
• Zhou, Z., Lin, S., Cotter, R. J., Raetz, C. R. H. (1999). Lipid A Modifications Characteristic of Salmonella typhimurium Are Induced by NH4VO3 in Escherichia coli K12. DETECTION OF 4-AMINO-4-DEOXY-L-ARABINOSE, PHOSPHOETHANOLAMINE AND PALMITATE. J. Biol. Chem. 274: 18503-18514 [Abstract] [Full Text]  
• Gibbons, H. S., Lin, S., Cotter, R. J., Raetz, C. R. H. (2000). Oxygen Requirement for the Biosynthesis of the S-2-Hydroxymyristate Moiety in Salmonella typhimurium Lipid A. FUNCTION OF LpxO, A NEW Fe2+/alpha -KETOGLUTARATE-DEPENDENT DIOXYGENASE HOMOLOGUE. J. Biol. Chem. 275: 32940-32949 [Abstract] [Full Text]  
• Kanipes, M. I., Lin, S., Cotter, R. J., Raetz, C. R. H. (2001). Ca2+-induced Phosphoethanolamine Transfer to the Outer 3-Deoxy-D-manno-octulosonic Acid Moiety of Escherichia coli Lipopolysaccharide. A NOVEL MEMBRANE ENZYME DEPENDENT UPON PHOSPHATIDYLETHANOLAMINE. J. Biol. Chem. 276: 1156-1163 [Abstract] [Full Text]  
• Breazeale, S. D., Ribeiro, A. A., Raetz, C. R. H. (2002). Oxidative Decarboxylation of UDP-Glucuronic Acid in Extracts of Polymyxin-resistant Escherichia coli. ORIGIN OF LIPID A SPECIES MODIFIED WITH 4-AMINO-4-DEOXY-L-ARABINOSE. J. Biol. Chem. 277: 2886-2896 [Abstract] [Full Text]