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Antimicrobial Agents and Chemotherapy, September 2006, p. 2983-2989, Vol. 50, No. 9
0066-4804/06/$08.00+0     doi:10.1128/AAC.01583-05
Copyright © 2006, American Society for Microbiology. All Rights Reserved.

In Silico Identification and Biological Evaluation of Antimicrobial Peptides Based on Human Cathelicidin LL-37

Thorgerdur Sigurdardottir,1 Pia Andersson,1 Mina Davoudi,2 Martin Malmsten,3 Artur Schmidtchen,2 and Mikael Bodelsson1*

Section of Anesthesiology and Intensive Care,1 Section for Dermatology and Venereology, Department of Clinical Sciences, Lund University, SE-221 85 Lund, Sweden,2 Department of Pharmacy, Uppsala University, Box 580, SE-751 23 Uppsala, Sweden3

Received 13 December 2005/ Returned for modification 15 March 2006/ Accepted 2 July 2006

Bacterial lipopolysaccharides (LPS) are important triggers of the widespread inflammatory response, which contributes to the development of multiple organ failure during sepsis. The helical 37-amino-acid-long human antimicrobial peptide LL-37 not only possesses a broad-spectrum antimicrobial activity but also binds and neutralizes LPS. However, the use of LL-37 in sepsis treatment is hampered by the fact that it is also cytotoxic. To find a less toxic analog of LL-37, we used in silico analysis to identify amphipathic helical regions of LL-37. A 21-amino-acid fragment (GKE) was synthesized, the biological actions of which were compared to those of two equally long peptides derived from the N and C termini of LL-37 as well as native LL-37. GKE displayed antimicrobial activity against Escherichia coli, Pseudomonas aeruginosa, Staphylococcus aureus, Candida albicans, and Candida parapsilosis that was similar to or even stronger than LL-37. GKE, as well as the equally long control peptides, attracted granulocytes in a fashion similar to that of LL-37, while only GKE was as potent as LL-37 in inhibiting LPS-induced vascular nitric oxide production. GKE caused less hemolysis and apoptosis in human cultured smooth muscle cells than LL-37. In summary, we have identified an active domain of LL-37, GKE, which displays antimicrobial activity in vitro and LPS-binding activity similar to those of LL-37 but is less toxic. GKE therefore holds promise as a template for the development of peptide antibiotics for the treatment of sepsis.

* Corresponding author. Mailing address: Department of Anesthesia and Intensive Care, University Hospital, SE-221 85 Lund, Sweden. Phone: 46 46 17 19 49. Fax: 46 46 17 60 50. E-mail: mikael.bodelsson{at}med.lu.se.

Antimicrobial Agents and Chemotherapy, September 2006, p. 2983-2989, Vol. 50, No. 9
0066-4804/06/$08.00+0     doi:10.1128/AAC.01583-05
Copyright © 2006, American Society for Microbiology. All Rights Reserved.



This article has been cited by other articles:

  • Epand, R. F., Wang, G., Berno, B., Epand, R. M. (2009). Lipid Segregation Explains Selective Toxicity of a Series of Fragments Derived from the Human Cathelicidin LL-37. Antimicrob. Agents Chemother. 53: 3705-3714 [Abstract] [Full Text]  
  • Stromstedt, A. A., Pasupuleti, M., Schmidtchen, A., Malmsten, M. (2009). Evaluation of Strategies for Improving Proteolytic Resistance of Antimicrobial Peptides by Using Variants of EFK17, an Internal Segment of LL-37. Antimicrob. Agents Chemother. 53: 593-602 [Abstract] [Full Text]  
  • Wang, G. (2008). Structures of Human Host Defense Cathelicidin LL-37 and Its Smallest Antimicrobial Peptide KR-12 in Lipid Micelles. J. Biol. Chem. 283: 32637-32643 [Abstract] [Full Text]  


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