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Antimicrobial Agents and Chemotherapy, June 2009, p. 2510-2516, Vol. 53, No. 6
0066-4804/09/$08.00+0     doi:10.1128/AAC.00863-08
Copyright © 2009, American Society for Microbiology. All Rights Reserved.

Prevention of Death in Bacterium-Infected Mice by a Synthetic Antimicrobial Peptide, L5, through Activation of Host Immunity ^,

Yukiko Okuyama-Nishida,^1, Nobuko Akiyama,^1,2*, Giichi Sugimori,³ Kazuhide Nomura,³ Kenji Ogawa,² Koichi J. Homma,⁴ Kazuhisa Sekimizu,⁵ Masafumi Tsujimoto,² and Shunji Natori¹

Natori Laboratory,¹ Cellular Biochemistry Laboratory, RIKEN, 2-1 Hirosawa, Wako-shi, Saitama 351-0198, Japan,² Shionogi & Co., Ltd., 5-12-4 Sagisu, Fukushima-ku, Osaka-shi, Osaka 553-0002, Japan,³ Faculty of Pharmaceutical Sciences, Teikyo University, 1019-1 Suwarashi, Sagamiko-cho, Sagamihara, Kanagawa 229-0195, Japan,⁴ Graduate School of Pharmaceutical Sciences, The University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo 113-0033, Japan⁵

Received 29 June 2008/ Returned for modification 13 August 2008/ Accepted 10 March 2009

In our previous study, we found that the antibacterial peptide KLKLLLLLKLK-NH₂ (L5) and its d-enantiomer (DL5) activate neutrophils to produce superoxide anions (O₂^–) and prevent death due to infection by methicillin-resistant Staphylococcus aureus, suggesting that these peptides may elicit in vivo antimicrobial activities through host inflammatory responses mediated by neutrophils. In this study, we investigated the mechanisms behind in vivo antimicrobial prophylaxis by the use of L5 for the treatment of bacterial infection introduced via intra-abdominal implantation. We found that the intraperitoneal treatment with L5 before bacterial infection markedly reduced rates of death due to infection. Treatments with L5 were highly effective in preventing death due to intraperitoneal inoculation of not only S. aureus Smith but also Enterococcus faecalis SR1004 and Escherichia coli EC14. The intra-abdominal administration of L5 induced accumulation of neutrophils, increased levels of reactive oxygen species, and augmented antibacterial activity in the abdominal cavity. In addition, administration of L5 upregulated the expression of the Mig/CXCL9 chemokine gene in thioglycolate-elicited peritoneal macrophages. Our results suggested that the prevention of death by treatment of infected mice with L5 might occur primarily through the activation of a host immune response.

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* Corresponding author. Mailing address: Cellular Biochemistry Laboratory, RIKEN, 2-1 Hirosawa, Wako-shi, Saitama 351-0198, Japan. Phone: 81 48 467 9515. Fax: 81 48 462 4670. E-mail: fnobuko{at}riken.jp

Published ahead of print on 16 March 2009.

Supplemental material for this article may be found at http://aac.asm.org/.

Y.O.-N. and N.A. contributed equally to this work.

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Antimicrobial Agents and Chemotherapy, June 2009, p. 2510-2516, Vol. 53, No. 6
0066-4804/09/$08.00+0     doi:10.1128/AAC.00863-08
Copyright © 2009, American Society for Microbiology. All Rights Reserved.