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

Published on Oct 3, 2002in Molecular Microbiology 3.82
· DOI :10.1046/j.1365-2958.2002.03146.x
Artur Schmidtchen41
Estimated H-index: 41
,
Inga-Maria Frick24
Estimated H-index: 24
(Lund University)
+ 2 AuthorsLars Björck61
Estimated H-index: 61
(Lund University)
Abstract
Summary Effectors of the innate immune system, the antibacterial 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 LL37 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 [D UA(2S)-GalNAc(4,6S)], or sucroseoctasulphate, inhibited 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.
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  • Citations (291)
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References49
Newest
Published on Dec 1, 2001in Acta Dermato-venereologica
Artur Schmidtchen41
Estimated H-index: 41
(Lund University),
Hélène Wolff3
Estimated H-index: 3
,
Carita Hansson5
Estimated H-index: 5
Pseudomonas aeruginosa colonizes 20-30% of all venous leg ulcers. Hypothetically, P. aeraginosa could release proteases and cytotoxic substances in the environment of chronic ulcers, thus negatively affecting the wound-healing activity in this patient group. Here we show that P. aeruginosa isolates from leg ulcers exhibit a highly variable expression of the proteinases elastase and alkaline proteinase. We propose that bacterial phenotype should be taken into account in future studies on the clin...
34 Citations Source Cite
Published on Nov 16, 2001
Margareta Frohm Nilsson1
Estimated H-index: 1
2 Citations
Published on Nov 1, 2001in Nature 41.58
Victor Nizet87
Estimated H-index: 87
(University of California, San Diego),
Takaaki Ohtake24
Estimated H-index: 24
(University of California, San Diego)
+ 7 AuthorsRichard L. Gallo96
Estimated H-index: 96
(University of California, San Diego)
In mammals, several gene families encode peptides with antibacterial activity, such as the β-defensins and cathelicidins1,2,3. These peptides are expressed on epithelial surfaces and in neutrophils, and have been proposed to provide a first line of defence against infection by acting as ‘natural antibiotics’4,5. The protective effect of antimicrobial peptides is brought into question by observations that several of these peptides are easily inactivated6,7,8 and have diverse cellular effects that...
959 Citations Source Cite
Published on Oct 1, 2001in Biochemistry 3.00
Akiko Kinoshita6
Estimated H-index: 6
,
Shuhei Yamada35
Estimated H-index: 35
+ 3 AuthorsKazuyuki Sugahara64
Estimated H-index: 64
Squid cartilage chondroitin sulfate E (CS-E) exhibits various biological activities, including anticoagulant activities, lymphoid regulatory activities, and neuroregulatory activities [Ueoka, C., Kaneda, N., Okazaki, I., Nadanaka, S., Muramatsu, T., and Sugahara, K. (2000) J. Biol. Chem. 275, 37407−37413]. These activities are expressed through molecular interactions with specific proteins, including heparin cofactor II, selectins, CD44, chemokines, and the heparin-binding growth factor midkine....
41 Citations Source Cite
Published on Jul 1, 2001in Journal of Investigative Dermatology 6.45
Robert A. Dorschner19
Estimated H-index: 19
(University of California, San Diego),
Vasumati Pestonjamasp4
Estimated H-index: 4
(University of California, San Diego)
+ 6 AuthorsRichard L. Gallo96
Estimated H-index: 96
(University of California, San Diego)
Cathelicidins are a family of peptides thought to provide an innate defensive barrier against a variety of potential microbial pathogens. The human and mouse cathelicidins (LL-37 and CRAMP, respectively) are expressed at select epithelial interfaces where they have been proposed to kill a number of gram-negative and gram-positive bacteria. To determine if these peptides play a part in the protection of skin against wound infections, the anti-microbial activity of LL-37 and CRAMP was determined a...
431 Citations Source Cite
Published on Jun 15, 2001in Blood 15.13
Ole E. Sørensen40
Estimated H-index: 40
,
Per Follin18
Estimated H-index: 18
+ 4 AuthorsNiels Borregaard79
Estimated H-index: 79
Cathelicidins are a family of antimicrobial proteins found in the peroxidase-negative granules of neutrophils. The known biologic functions reside in the C-terminus, which must be cleaved from the holoprotein to become active. Bovine and porcine cathelicidins are cleaved by elastase from the azurophil granules to yield the active antimicrobial peptides. The aim of this study was to identify the physiological setting for cleavage of the only human cathelicidin, hCAP-18, to liberate the antibacter...
616 Citations Source Cite
Published on May 7, 2001in Journal of Experimental Medicine 10.79
Andreas Peschel63
Estimated H-index: 63
,
Ralph W. Jack21
Estimated H-index: 21
+ 9 AuthorsAndrej Tarkowski65
Estimated H-index: 65
Defensins, antimicrobial peptides of the innate immune system, protect human mucosal epithelia and skin against microbial infections and are produced in large amounts by neutrophils. The bacterial pathogen Staphylococcus aureus is insensitive to defensins by virtue of an unknown resistance mechanism. We describe a novel staphylococcal gene, mprF, which determines resistance to several host defense peptides such as defensins and protegrins. An mprF mutant strain was killed considerably faster by ...
522 Citations Source Cite
Published on May 1, 2001in Journal of Leukocyte Biology 4.22
De Yang1
Estimated H-index: 1
(National Institutes of Health),
Oleg Chertov28
Estimated H-index: 28
(National Institutes of Health),
Joost J. Oppenheim118
Estimated H-index: 118
(National Institutes of Health)
216 Citations Source Cite
Published on May 1, 2001in Nature 41.58
Pyong Woo Park33
Estimated H-index: 33
(Baylor College of Medicine),
Gerald B. Pier74
Estimated H-index: 74
(Brigham and Women's Hospital)
+ 1 AuthorsMerton Bernfield63
Estimated H-index: 63
(Boston Children's Hospital)
Cell-surface heparan sulphate proteoglycans (HSPGs) are ubiquitous and abundant receptors/co-receptors of extracellular ligands1,2, including many microbes3,4,5,6,7,8,9,10. Their role in microbial infections is poorly defined, however, because no cell-surface HSPG has been clearly connected to the pathogenesis of a particular microbe. We have previously shown that Pseudomonas aeruginosa, through its virulence factor LasA, enhances the in vitro shedding of syndecan-1—the predominant cell-surface ...
181 Citations Source Cite
Published on Feb 1, 2001in Molecular Microbiology 3.82
Artur Schmidtchen41
Estimated H-index: 41
(Lund University),
Inga-Maria Frick24
Estimated H-index: 24
(Lund University),
Lars Björck61
Estimated H-index: 61
(Lund University)
Defensins represent an evolutionarily conserved group of small peptides with potent antibacterial activities. We report here that extracellular proteinases secreted by the human pathogens Pseudomonas aeruginosa, Enterococcus faecalis and Streptococcus pyogenes release dermatan sulphate by degrading dermatan sulphate-containing proteoglycans, such as decorin. Dermatan sulphate was found to bind to neutrophil-derived alpha-defensin, and this binding completely neutralized its bactericidal activity...
126 Citations Source Cite
Cited By291
Newest
Published on Mar 27, 2019in Current Protein & Peptide Science 2.70
Anna Clara M. Galdino4
Estimated H-index: 4
(Federal University of Rio de Janeiro),
Matheus P. de Oliveira1
Estimated H-index: 1
(University of California, Los Angeles)
+ 3 AuthorsAndré Luis Souza dos Santos25
Estimated H-index: 25
(Federal University of Rio de Janeiro)
Source Cite
Published on Feb 28, 2019in Journal of the Royal Society Interface 3.35
Fan Wu (University of California, Davis), Cheemeng Tan13
Estimated H-index: 13
(University of California, Davis)
The collective tolerance towards antimicrobial peptides (APs) is thought to occur primarily through mechanisms associated with live bacterial cells. In contrast to the focus on live cells, we discover that the LL37 antimicrobial peptide kills a subpopulation of Escherichia coli, forming dead cells that absorb the remaining LL37 from the environment. Combining mathematical modelling with population and single-cell experiments, we show that bacteria absorb LL37 at a timing that coincides with the ...
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Published on Feb 1, 2019in Chemistry & Biology 5.92
Myung-Ryul Lee13
Estimated H-index: 13
(University of Wisconsin-Madison),
Namrata Raman6
Estimated H-index: 6
(University of Wisconsin-Madison)
+ 2 AuthorsSean P. Palecek42
Estimated H-index: 42
(University of Wisconsin-Madison)
Summary Synthetic peptidomimetics of antimicrobial peptides (AMPs) are promising antimicrobial drug candidates because they promote membrane disruption and exhibit greater structural and proteolytic stability than natural AMPs. We previously reported selective antifungal 14-helical β-peptides, but the mechanism of antifungal toxicity of β-peptides remains unknown. To provide insight into the mechanism, we studied antifungal β-peptide binding to artificial membranes and living Candida albicans ce...
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Published on Nov 2, 2018in Journal of Wound Care 1.67
Hannah Trøstrup3
Estimated H-index: 3
(University of Copenhagen),
Per Holstein8
Estimated H-index: 8
(University of Copenhagen)
+ 2 AuthorsMagnus S. Ågren14
Estimated H-index: 14
(University of Copenhagen)
Objective: To compare matrix metalloproteinase (MMP)-9 and the antiproteinase tissue inhibitor of metalloproteinases (TIMP)-1 in wound fluids and sera from patients with chronic non-healing or acute healing wounds. In addition, the functional consequences on MMP-9 activity and general gelatinase activity were assessed. Method: In this observational study, samples were collected from patients with venous leg ulcers (VLUs), patients with type 2 diabetes with neuropathic foot ulcers (DFUs), and fro...
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Published on Nov 1, 2018in The Journal of Antibiotics 2.03
James Shurko1
Estimated H-index: 1
(University of Texas at Austin),
Ralph Galega (University of Texas at Austin)+ 1 AuthorsGrace C. Lee9
Estimated H-index: 9
(University of Texas at Austin)
Treatment of Staphylococcus aureus infections continues to be a challenge due to antimicrobial resistance. Endogenous antimicrobial peptides may offer a new option for treating S. aureus infections but several factors limit their clinical utility. Herein, we studied the activity of the antimicrobial peptide LL-37 and two truncated derivatives, LL-13 and LL-17 alone and in combination with vancomycin against a range of drug-resistant S. aureus strains including methicillin resistant S. aureus (MR...
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Published on Nov 1, 2018in Microbiology 0.85
Marlon H. Cardoso8
Estimated H-index: 8
(Universidade Católica de Brasília),
Keyla C. de Almeida3
Estimated H-index: 3
(Universidade Católica de Brasília)
+ 4 AuthorsOctávio L. Franco29
Estimated H-index: 29
(Universidade Católica de Brasília)
Antimicrobial peptides (AMPs) have attracted considerable attention because of their multiple and complex mechanisms of action toward resistant bacteria. However, reports have increasingly highlighted how bacteria can escape AMP administration. Here, the molecular mechanisms involved in Escherichia coli resistance to magainin I were investigated through comparative transcriptomics. Sub-inhibitory concentrations of magainin I were used to generate four experimental groups, including magainin I-su...
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Published on Oct 22, 2018in Frontiers in Immunology 5.51
Emmanuel Faure2
Estimated H-index: 2
(McGill University),
Kelly Kwong1
Estimated H-index: 1
(McGill University),
Dao Nguyen1
Estimated H-index: 1
(McGill University)
Bacteria that readily adapts to different natural environments, can also exploit this versatility upon infection of the host to persist. Pseudomonas aeruginosa, a ubiquitous Gram-negative bacterium, is harmless to healthy individuals, and yet a formidable opportunistic pathogen in compromised hosts. When pathogenic, P. aeruginosa causes invasive and highly lethal disease in certain compromised hosts. In others, such as individuals with the genetic disease cystic fibrosis, this pathogen causes ch...
2 Citations Source Cite
Published on Oct 5, 2018in Journal of Biological Chemistry 4.01
So Young Kim3
Estimated H-index: 3
,
Fuming Zhang34
Estimated H-index: 34
(Rensselaer Polytechnic Institute)
+ 7 AuthorsMyriam Cotten16
Estimated H-index: 16
(College of William & Mary)
2 Citations Source Cite
Published on Sep 1, 2018in Acta Tropica 2.51
Germán Alberto Téllez2
Estimated H-index: 2
,
Jesica Alejandra Zapata1
Estimated H-index: 1
+ 7 AuthorsJhon Carlos Castaño5
Estimated H-index: 5
Abstract Maggots from the Lucilia sp. genus are used for debridement of infected and necrotic wounds. Broad-spectrum antimicrobial activity has been described in the excretion/secretions (ES 1 ) of these larvae. This study identifies the genetic sequence of a cecropin-like antimicrobial peptide from Lucilia eximia. Total RNA was extracted and used for PCR-RACE amplification of a cecropin, the native peptide was immunolocalized in the tissues and secretions of the larvae, and a synthetic analog w...
2 Citations Source Cite