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Proteinases of common pathogenic bacteria degrade and inactivate the antibacterial peptide LL-37

Schmidtchen, Artur LU ; Frick, Inga-Maria LU ; Andersson, Emma ; Tapper, Hans LU and Björck, Lars LU (2002) In Molecular Microbiology 46(1). p.157-168
Abstract
Effectors of the innate immune system, the anti-bacterial peptides, have pivotal roles in preventing infection at epithelial surfaces. Here we show that proteinases of the significant human pathogens Pseudomonas aeruginosa, Enterococcus faecalis, Proteus mirabilis and Streptococcus pyogenes, degrade the antibacterial peptide LL-37. Analysis by mass spectrometry of fragments generated by P. aeruginosa elastase in vitro revealed that the initial cleavages occurred at Asn-Leu and Asp-Phe, followed by two breaks at Arg-Ile, thus inactivating the peptide. Proteinases of the other pathogens also degraded LL-37 as determined by SDS-PAGE. Ex vivo, P. aeruginosa elastase induced LL-37 degradation in human wound fluid, leading to enhanced bacterial... (More)
Effectors of the innate immune system, the anti-bacterial peptides, have pivotal roles in preventing infection at epithelial surfaces. Here we show that proteinases of the significant human pathogens Pseudomonas aeruginosa, Enterococcus faecalis, Proteus mirabilis and Streptococcus pyogenes, degrade the antibacterial peptide LL-37. Analysis by mass spectrometry of fragments generated by P. aeruginosa elastase in vitro revealed that the initial cleavages occurred at Asn-Leu and Asp-Phe, followed by two breaks at Arg-Ile, thus inactivating the peptide. Proteinases of the other pathogens also degraded LL-37 as determined by SDS-PAGE. Ex vivo, P. aeruginosa elastase induced LL-37 degradation in human wound fluid, leading to enhanced bacterial survival. The degradation was blocked by the metalloproteinase inhibitors GM6001 and 1, 10-phenantroline (both of which inhibited P. aeruginosa elastase, P. mirabilis proteinase, and E. faecalis gelatinase), or the inhibitor E64 (which inhibited S. pyogenes cysteine proteinase). Additional experiments demonstrated that dermatan sulphate and disaccharides of the structure [DeltaUA(2S)-GalNAc(4,6S)], or sucroseoctasulphate, in-hibited the degradation of LL-37. The results indicate that proteolytic degradation of LL-37 is a common virulence mechanism and that molecules which block this degradation could have therapeutic potential. (Less)
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; ; ; and
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published
subject
keywords
Endopeptidases/*metabolism, Glycosaminoglycans/pharmacology, Microbial Sensitivity Tests, Human, Molecular Sequence Data, Pancreatic Elastase/metabolism, Neutrophils, Protease Inhibitors/pharmacology, Pseudomonas aeruginosa/enzymology/pathogenicity, Spectrum Analysis, Mass, Sulfur/metabolism, Wound Infection/microbiology, Virulence, Disaccharides/chemistry/pharmacology, Bacterial Infections/microbiology, Bacteria/*drug effects/*metabolism/pathogenicity, Antimicrobial Cationic Peptides/genetics/*metabolism/*pharmacology, Amino Acid Sequence
in
Molecular Microbiology
volume
46
issue
1
pages
157 - 168
publisher
Wiley-Blackwell
external identifiers
  • wos:000178372600014
  • pmid:12366839
  • scopus:0036030617
ISSN
1365-2958
DOI
10.1046/j.1365-2958.2002.03146.x
language
English
LU publication?
yes
id
205c61fc-9504-4205-b72e-f9d7695f7a30 (old id 112122)
alternative location
http://www.ncbi.nlm.nih.gov/sites/entrez?Db=pubmed&Cmd=ShowDetailView&TermToSearch=12366839&ordinalpos=3&itool=EntrezSystem2.PEntrez.Pubmed.Pubmed_ResultsPanel.Pubmed_RVDocSum
date added to LUP
2016-04-01 11:49:21
date last changed
2022-04-28 20:28:24
@article{205c61fc-9504-4205-b72e-f9d7695f7a30,
  abstract     = {{Effectors of the innate immune system, the anti-bacterial peptides, have pivotal roles in preventing infection at epithelial surfaces. Here we show that proteinases of the significant human pathogens Pseudomonas aeruginosa, Enterococcus faecalis, Proteus mirabilis and Streptococcus pyogenes, degrade the antibacterial peptide LL-37. Analysis by mass spectrometry of fragments generated by P. aeruginosa elastase in vitro revealed that the initial cleavages occurred at Asn-Leu and Asp-Phe, followed by two breaks at Arg-Ile, thus inactivating the peptide. Proteinases of the other pathogens also degraded LL-37 as determined by SDS-PAGE. Ex vivo, P. aeruginosa elastase induced LL-37 degradation in human wound fluid, leading to enhanced bacterial survival. The degradation was blocked by the metalloproteinase inhibitors GM6001 and 1, 10-phenantroline (both of which inhibited P. aeruginosa elastase, P. mirabilis proteinase, and E. faecalis gelatinase), or the inhibitor E64 (which inhibited S. pyogenes cysteine proteinase). Additional experiments demonstrated that dermatan sulphate and disaccharides of the structure [DeltaUA(2S)-GalNAc(4,6S)], or sucroseoctasulphate, in-hibited the degradation of LL-37. The results indicate that proteolytic degradation of LL-37 is a common virulence mechanism and that molecules which block this degradation could have therapeutic potential.}},
  author       = {{Schmidtchen, Artur and Frick, Inga-Maria and Andersson, Emma and Tapper, Hans and Björck, Lars}},
  issn         = {{1365-2958}},
  keywords     = {{Endopeptidases/*metabolism; Glycosaminoglycans/pharmacology; Microbial Sensitivity Tests; Human; Molecular Sequence Data; Pancreatic Elastase/metabolism; Neutrophils; Protease Inhibitors/pharmacology; Pseudomonas aeruginosa/enzymology/pathogenicity; Spectrum Analysis; Mass; Sulfur/metabolism; Wound Infection/microbiology; Virulence; Disaccharides/chemistry/pharmacology; Bacterial Infections/microbiology; Bacteria/*drug effects/*metabolism/pathogenicity; Antimicrobial Cationic Peptides/genetics/*metabolism/*pharmacology; Amino Acid Sequence}},
  language     = {{eng}},
  number       = {{1}},
  pages        = {{157--168}},
  publisher    = {{Wiley-Blackwell}},
  series       = {{Molecular Microbiology}},
  title        = {{Proteinases of common pathogenic bacteria degrade and inactivate the antibacterial peptide LL-37}},
  url          = {{https://lup.lub.lu.se/search/files/2657079/623699.pdf}},
  doi          = {{10.1046/j.1365-2958.2002.03146.x}},
  volume       = {{46}},
  year         = {{2002}},
}