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Infection and Immunity, December 1999, p. 6445-6453, Vol. 67, No. 12
0019-9567/99/$04.00+0
Copyright © 1999, American Society for Microbiology. All rights reserved.

Interaction of Cationic Peptides with Lipoteichoic Acid and Gram-Positive Bacteria

Monisha G. Scott, Michael R. Gold, and Robert E. W. Hancock*

Department of Microbiology and Immunology, University of British Columbia, Vancouver, British Columbia V6T 1Z3, Canada

Received 7 June 1999/Returned for modification 23 July 1999/Accepted 23 September 1999

Compounds with antiendotoxin properties have been extensively studied for their potential as therapeutic agents for sepsis attributable to gram-negative bacteria. However, with the increasing incidence of gram-positive sepsis, there is interest in identifying compounds with a broad spectrum of action against both gram-positive and gram-negative bacteria. A series of synthetic alpha -helical cationic peptides related to bee melittin and silk moth cecropin have previously been shown to bind lipopolysaccharide (LPS) with high affinity, inhibit LPS-induced tumor necrosis factor alpha (TNF-alpha ) production in vitro and in vivo, and kill gram-negative bacteria. In this study, we analyzed whether these peptides were active against gram-positive bacteria; whether they could bind to lipoteichoic acid (LTA), the major proinflammatory structure on gram-positive bacteria; and whether they could block the ability of LTA to promote the release of cytokines by the RAW 264.7 murine macrophage cell line. We found that the cationic peptides demonstrated moderate growth-inhibitory activity toward gram-positive bacteria. In addition, the peptides bound LTA with high affinity. This correlated with the ability of the peptides to block LTA-induced production of TNF and interleukin-6 by RAW 264.7 cells but did not correlate with their ability to kill the bacteria. The peptides also effectively inhibited LTA-induced TNF production in a whole human blood assay. The peptides were also able to partly block the ability of heat-killed Staphylococcus aureus, as well as soluble products of live S. aureus, to stimulate cytokine production by macrophages. Our results indicate that these cationic peptides may be useful to prevent sepsis and inflammation caused by both gram-negative and gram-positive bacteria.

* Corresponding author. Mailing address: Department of Microbiology and Immunology, University of British Columbia, 6174 University Blvd., Vancouver, British Columbia V6T 1Z3, Canada. Phone: (604) 822-2682. Fax: (604) 822-6041. E-mail: bob{at}cmdr.ubc.ca.

Infection and Immunity, December 1999, p. 6445-6453, Vol. 67, No. 12
0019-9567/99/$04.00+0
Copyright © 1999, American Society for Microbiology. All rights reserved.


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