Defensine

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(a) Monomers and (b) dimeric structure of the human β-defensin HBD-2

Defensins are small 33–47 amino acid long peptides that have three intramolecular disulfide bridges . They occur as antimicrobial peptides in all animal organisms and higher plants and serve to ward off microbial pathogens , especially bacteria , but also fungi and toxins . It is also assumed that they inhibit the replication of viruses and attract and activate monocytes .

In mammals they are found in large numbers on the skin and mucous membrane surfaces and they form a large proportion of the proteins (about 30%) in the granules of the neutrophil granulocytes . During an inflammatory reaction , the body's own production of defensins increases.

classification

Defensins can be divided into four families based on their relationship , each of which has its own entry in the membrane transport protein database : animal defensins ( 1.C.19 ), plant defensins ( 1.C.45 ), insect defensins ( 1.C.47 ) and the pore-forming mammalian-specific β-defensins ( 1.A.68 ).

function

The mechanism of action of the defensins is not yet fully understood. It is known that defensins have many cationic and hydrophobic amino acid residues . Such peptides are molecules that are composed of two functional parts and whose positive charges interact with the negative charges of the pathogen membranes .

The defensins prefer membranes that are characterized by a low proportion of cholesterol and thus differ from those of eukaryotic organisms. Once they have penetrated the membrane, they also interact with anionic molecules within the pathogen cell, such as DNA and RNA . Due to this relatively unspecific effect, the spectrum of activity is broad ( broad spectrum antibiotic ) and it remains difficult for the pathogen to counteract the mechanism of the defensins.

Surprisingly, it was found that the gene for the dominantly black coat color of the domestic dog also encodes a defensin called β-defensin 103 (CBD103) . This gene product binds to the melanocortin receptor 1 , which is encoded by the extension locus , and has a strong effect on the switching from pheomelanin to eumelanin .

research

Plectasis of the Pseudoplectania nigrella

In 2001, as part of a study by the Danish company Novozymes, the peptide plectasin was discovered and described in a publication in 2005, which, as a defense molecule, belongs to the so-called defensins that are widely used in fungi from the order of cuplet-like , animals and probably also plants. The clarification of its mode of action has now shown that this active ingredient triggers a bacterial defense with two effects. On the one hand, it kills the pathogens by attaching the protein molecule to the cell wall component lipid II, thus preventing it from being built into new bacterial walls. On the other hand, it alarms and activates the immune system at the same time . Plectasin showed a particularly high effectiveness against pneumococci both in vitro and in an in vivo mouse infection model . Preclinical studies have also shown that multidrug-resistant bacteria have had significant difficulties developing resistance to this defensin. The researchers therefore see this active ingredient as a promising lead substance for new antibiotics.

Current research attempts to use the defensins as an antidote, for example, against the bacterial anthrax toxin.

literature

Individual evidence

  1. ↑ Sebastian Suerbaum, Helmut Hahn a. a .: Medical microbiology and infectious diseases . 7th edition, Springer, Berlin 2012, ISBN 978-3-642-24166-6 , p. 91.
  2. ↑ SI Candille, CB Kaelin et al. a .: A -defensin mutation causes black coat color in domestic dogs. In: Science . Nov 30, 2007, Volume 318, No. 5855, pp. 1418-1423, Epub: October 18, 2007, PMID 17947548 .
  3. ↑ Novozymes reveals knowledge on new antibiotic against resistant bacteria . In: novozymes.com . May 28, 2010. Archived from the original on November 14, 2012. Info: The archive link was automatically inserted and not yet checked. Please check the original and archive link according to the instructions and then remove this notice. Retrieved August 31, 2012. @1@ 2Template: Webachiv / IABot / www.novozymes.com
  4. ↑ Per H. Mygind, Rikke L. Fischer u. a .: Plectasin is a peptide antibiotic with therapeutic potential from a saprophytic fungus. In: Nature . Volume 437, No. 7061, 2005, pp. 975-80, doi : 10.1038 / nature04051 .
  5. ↑ a b T. Schneider u. a .: Plectasin, a Fungal Defensin, Targets the Bacterial Cell Wall, Precursor Lipid II. In: Science. 2010, doi: 10.1126 / science.1185723 .
  6. ↑ Plectasin NZ2114 - Novel Microbial Agent . In: drugdevelopment-technology.com . Retrieved May 28, 2010.
  7. ↑ D. Andes, W. Craig, LA Nielsen, HH Kristensen: In Vivo Pharmacodynamic Characterization of a Novel Plectasin Antibiotic, NZ2114, in a Murine Infection Model. In: Antimicrobial Agents and Chemotherapy. Volume 53, 2009, pp. 3003-3009, doi : 10.1128 / AAC.01584-08 . PMC 2704636 (free full text).