Lipid A Acylation and Bacterial Resistance against Vertebrate Antimicrobial Peptides

Guo, Lin; Lim, Kheng B.; Poduje, Cristina M; Daniel, Morad; Gunn, John S.; Hackett, Murray; Miller, Samuel I.

doi:10.1016/s0092-8674(00)81750-x

Cited by 568 publications

(559 citation statements)

References 45 publications

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“…Chemical modification of the arginine residues with BAD not only inhibited the antimicrobial activity of granulysin, but also interfered with the protein interaction with the bacterial cell wall or membrane. Previous studies indicate the role of the negatively charged bacterial cell membrane with cationic antimicrobial peptides (19). Taken together, these data indicate that ionic interactions between granulysin and bacterial membranes are required for optimal antimicrobial activity.…”

Section: Discussionsupporting

confidence: 62%

Granulysin, a T Cell Product, Kills Bacteria by Altering Membrane Permeability

Ernst

Thoma-Uszynski

Teitelbaum

et al. 2000

The Journal of Immunology

194

171

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Granulysin, a protein located in the acidic granules of human NK cells and cytotoxic T cells, has antimicrobial activity against a broad spectrum of microbial pathogens. A predicted model generated from the nuclear magnetic resonance structure of a related protein, NK lysin, suggested that granulysin contains a four α helical bundle motif, with the α helices enriched for positively charged amino acids, including arginine and lysine residues. Denaturation of the polypeptide reduced the α helical content from 49 to 18% resulted in complete inhibition of antimicrobial activity. Chemical modification of the arginine, but not the lysine, residues also blocked the antimicrobial activity and interfered with the ability of granulysin to adhere to Escherichia coli and Mycobacterium tuberculosis. Granulysin increased the permeability of bacterial membranes, as judged by its ability to allow access of cytosolic β-galactosidase to its impermeant substrate. By electron microscopy, granulysin triggered fluid accumulation in the periplasm of M. tuberculosis, consistent with osmotic perturbation. These data suggest that the ability of granulysin to kill microbial pathogens is dependent on direct interaction with the microbial cell wall and/or membrane, leading to increased permeability and lysis.

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Section: Discussionsupporting

confidence: 62%

Granulysin, a T Cell Product, Kills Bacteria by Altering Membrane Permeability

Ernst

Thoma-Uszynski

Teitelbaum

et al. 2000

The Journal of Immunology

194

171

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“…PhoP orthologues regulate expression of genes essential for virulence and magnesium acquisition in several Gram-negative bacteria [14,20,11]. Some of the PhoP-induced enzymes promote increased bacterial resistance to antimicrobial peptides, a key component of host's innate immunity [10,17,21,22]. For example, PhoP-activated LPS modifications, including the addition of aminoarabinose and palmitate to lipid A, promote resistance to the antibiotic polymyxin and other cationic antimicrobial peptides [10,21,23].…”

Section: Quantitative Proteomic Analysis Defined P Aeruginosa Virulementioning

confidence: 99%

Proteomic analysis of Pseudomonas aeruginosa grown under magnesium limitation

Guina

Miller

et al. 2003

J. Am. Soc. Mass Spectrom.

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In this study, large-scale qualitative and quantitative proteomic technology was applied to the analysis of the opportunistic bacterial pathogen Pseudomonas aeruginosa grown under magnesium limitation, an environmental condition previously shown to induce expression of various virulence factors. For quantitative analysis, whole cell and membrane proteins were differentially labeled with isotope-coded affinity tag (ICAT) reagents and ICAT reagent-labeled peptides were separated by two-dimensional chromatography prior to analysis by electrospray ionization-tandem mass spectrometry (ESI-MS/MS) in an ion trap mass spectrometer (ITMS). To increase the number of protein identifications, gas-phase fractionation (GPF) in the m/z dimension was employed for analysis of ICAT peptides derived from whole cell extracts. The experiments confirmed expression of 1331 P. aeruginosa proteins of which 145 were differentially expressed upon limitation of magnesium. A number of conserved Gram-negative magnesium stress-response proteins involved in bacterial virulence were among the most abundant proteins induced in low magnesium. Comparative ICAT analysis of membrane versus whole cell protein indicated that growth of P. aeruginosa in low magnesium resulted in altered subcellular compartmentalization of large enzyme complexes such as ribosomes. This result was confirmed by 2-D PAGE analysis of P. aeruginosa outer membrane proteins. This study shows that large-scale quantitative proteomic technology can be successfully applied to the analysis of whole bacteria and to the discovery of functionally relevant biologic phenotypes.

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“…It was recently shown that treating Escherichia coli with EDTA leads to activation of PagP via a membrane perturbation mechanism (25). Palmitoylation of lipid A leads to an increased resistance of the bacterium to cationic antimicrobial peptides (20). Furthermore, palmitoylated LPS is attenuated for signaling through TLR4/MD-2 (24).…”

mentioning

confidence: 99%

Expression of the Lipopolysaccharide-Modifying Enzymes PagP and PagL Modulates the Endotoxic Activity ofBordetella pertussis

Geurtsen¹,

Steeghs

Hamstra³

et al. 2006

Infect Immun

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Lipopolysaccharide (LPS) is one of the major constituents of the gram-negative bacterial cell envelope. Its endotoxic activity causes the relatively high reactogenicity of whole-cell vaccines. Several bacteria harbor LPS-modifying enzymes that modulate the endotoxic activity of the LPS. Here we evaluated whether two such enzymes, i.e., PagP and PagL, could be useful tools for the development of an improved and less reactogenic whole-cell pertussis vaccine. We showed that expression of PagP and PagL in Bordetella pertussis leads to increased and decreased endotoxic activity of the LPS, respectively. As expected, PagP activity also resulted in increased endotoxic activity of whole bacterial cells. However, more unexpectedly, this was also the case for PagL. This paradoxical result may be explained, in part, by an increased release of LPS, which we observed in the PagL-expressing cells.

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Lipid A Acylation and Bacterial Resistance against Vertebrate Antimicrobial Peptides

Cited by 568 publications

References 45 publications

Granulysin, a T Cell Product, Kills Bacteria by Altering Membrane Permeability

Granulysin, a T Cell Product, Kills Bacteria by Altering Membrane Permeability

Proteomic analysis of Pseudomonas aeruginosa grown under magnesium limitation

Expression of the Lipopolysaccharide-Modifying Enzymes PagP and PagL Modulates the Endotoxic Activity ofBordetella pertussis

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