Chicken cathelicidin-2-derived peptides with enhanced immunomodulatory and antibacterial activities against biological warfare agents.
Host defence peptides (HDPs) are considered to be excellent candidates for the development of novel therapeutic agents. Recently, it was demonstrated that the peptide C1-15, an N-terminal segment of chicken HDP cathelicidin-2, exhibits potent antibacterial activity while lacking cytotoxicity towards eukaryotic cells. In the present study, we report that C1-15 is active against bacteria such as Bacillus anthracis and Yersinia pestis that may potentially be used by bioterrorists. Substitution of single and multiple phenylalanine (Phe) residues to tryptophan (Trp) in C1-15 resulted in variants with improved antibacterial activity against B. anthracis and Y. pestis as well as decreased salt sensitivity. In addition, these peptides exhibited enhanced neutralisation of lipopolysaccharide (LPS)-induced release of pro-inflammatory cytokines in human peripheral blood mononuclear cells (PBMCs). The antibacterial and LPS-neutralising activities of these C1-15-derived peptides are exerted at concentrations far below the concentrations that are toxic to human PBMCs. Taken together, we show that Phe-->Trp substitutions in C1-15 variants enhances the antibacterial and LPS-neutralising activities against pathogenic bacteria, including those that may potentially be used as biological warfare agents.
Molhoek
E Margo
EM
TNO Defence, Security and Safety, Rijswijk, The Netherlands.
van Dijk
Albert
A
Veldhuizen
Edwin J A
EJ
Dijk-Knijnenburg
Helma
H
Mars-Groenendijk
Roos H
RH
Boele
Linda C L
LC
Kaman-van Zanten
Wendy E
WE
Haagsman
Henk P
HP
Bikker
Floris J
FJ
D019943:Amino Acid Substitution / Q000235:genetics; D000818:Animals; D000900:Anti-Bacterial Agents / Q000494:pharmacology* / Q000633:toxicity; D023181:Antimicrobial Cationic Peptides / Q000235:genetics / Q000494:pharmacology* / Q000633:toxicity; D001408:Bacillus anthracis / Q000187:drug effects*; D054045:Biological Warfare Agents; D002645:Chickens; D015169:Colony Count, Microbial; D016207:Cytokines / Q000378:metabolism; D006801:Humans; D007155:Immunologic Factors / Q000235:genetics / Q000494:pharmacology* / Q000633:toxicity; D007963:Leukocytes, Mononuclear / Q000187:drug effects / Q000276:immunology; D008070:Lipopolysaccharides / Q000037:antagonists & inhibitors; D055624:Methicillin-Resistant Staphylococcus aureus / Q000187:drug effects; D050296:Microbial Viability / Q000187:drug effects; D014734:Vibrio cholerae / Q000187:drug effects; D015010:Yersinia pestis / Q000187:drug effects*
D000900:Anti-Bacterial Agents; D023181:Antimicrobial Cationic Peptides; D054045:Biological Warfare Agents; C504855:CMAP27 protein, chicken; D016207:Cytokines; D007155:Immunologic Factors; D008070:Lipopolysaccharides