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Antimicrobial Agents and Chemotherapy, November 2007, p. 4148-4156, Vol. 51, No. 11
0066-4804/07/$08.00+0     doi:10.1128/AAC.00635-07
Copyright © 2007, American Society for Microbiology. All Rights Reserved.

Antimicrobial Effect of Halocidin-Derived Peptide in a Mouse Model of Listeria Infection{triangledown}

Woong Sik Jang,1,{dagger} Sang-Chul Lee,2,{dagger} Young Shin Lee,1 Yong Pyo Shin,1 Kyoung Hwa Shin,1 Boo Hee Sung,2 Byung S. Kim,2 Soo Han Lee,3 and In Hee Lee1*

Department of Biotechnology, Hoseo University, Asan City, Chungnam, South Korea,1 Immunomodulation Research Center, University of Ulsan, Ulsan, South Korea,2 Department of Clinical Pharmacology and Therapeutics, Asan Medical Center, Seoul, South Korea3

Received 14 May 2007/ Returned for modification 25 July 2007/ Accepted 29 August 2007

Halocidin is an antimicrobial peptide found in the tunicate. A series of experiments were previously conducted in an attempt to develop a novel antibiotic derived from halocidin, as the peptide was determined to evidence profound antimicrobial activity against a variety of antibiotic-resistant microbes, with significantly less toxicity to human blood cells. In this study, we assessed the validity of one of the halocidin congeners, called Khal, as a new antibiotic for the treatment of systemic bacterial infections. Our in vitro antimicrobial tests showed that the MICs of Khal against several gram-positive bacteria were below 16 µg/ml in the presence of salt. We also determined that Khal retained sufficient target selectivity to discern microbial and human blood cells and was therefore capable of efficiently killing invading pathogens. Furthermore, Khal caused no aggregation problems upon incubation with human serum and also proved to be resistant to proteolysis by enzymes occurring in human serum. In the following experiments conducted with a mouse model of Listeria monocytogenes infection, we demonstrated that a single intravenous inoculation with Khal resulted in significant therapeutic effects on the survival of mice. In addition, our bacterial-enumeration analysis showed that after Listeria infection, livers and spleens from Khal-treated mice generated a great deal fewer recoverable CFU. Finally, the antibiotic effects of Khal were evaluated under confocal microscopy after we immunostained the liver sections with anti-Khal antibody. It was concluded that Khal bound specifically to the surfaces of bacteria colonized in the mouse liver and killed the bacteria rapidly.

* Corresponding author. Mailing address: Department of Biotechnology, Hoseo University, 165 Sechuli, Baebangmyun, Asan City, Chungnam 336-795, South Korea. Phone: 82-41-540-5626. Fax: 82-41-548-6231. E-mail: leeih{at}office.hoseo.ac.kr

{triangledown} Published ahead of print on 10 September 2007.

{dagger} W.S. Jang and S.-C. Lee contributed equally to this study.

Antimicrobial Agents and Chemotherapy, November 2007, p. 4148-4156, Vol. 51, No. 11
0066-4804/07/$08.00+0     doi:10.1128/AAC.00635-07
Copyright © 2007, American Society for Microbiology. All Rights Reserved.





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