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Antimicrobial Agents and Chemotherapy, July 2005, p. 2921-2927, Vol. 49, No. 7
0066-4804/05/$08.00+0     doi:10.1128/AAC.49.7.2921-2927.2005
Copyright © 2005, American Society for Microbiology. All Rights Reserved.

Antimicrobial Peptide Therapeutics for Cystic Fibrosis

Lijuan Zhang,1* Jody Parente,1 Scott M. Harris,1 Donald E. Woods,2 Robert E. W. Hancock,3 and Timothy J. Falla1

Helix Biomedix Inc., 22122 20th Avenue SE, Bothell, Washington 98021,1 Department of Microbiology and Infectious Diseases, University of Calgary Health Sciences Centre, Calgary, Alberta, Canada,2 Department of Microbiology and Immunology, University of British Columbia, 2259 Lower Mall Research Station, Vancouver, Canada3

Received 30 November 2004/ Returned for modification 25 February 2005/ Accepted 11 April 2005

Greater than 90% of lung infections in cystic fibrosis (CF) patients are caused by Pseudomonas aeruginosa, and the majority of these patients subsequently die from lung damage. Current therapies are either targeted at reducing obstruction, reducing inflammation, or reducing infection. To identify potential therapeutic agents for the CF lung, 150 antimicrobial peptides consisting of three distinct structural classes were screened against mucoid and multidrug-resistant clinical isolates of P. aeruginosa, Stenotrophomonas maltophilia, Achromobacter xylosoxidans, and Staphylococcus aureus. Five peptides that retained potent antimicrobial activities in physiological salt and divalent cation environment were further characterized in vivo using a rat chronic lung infection model. All animals were inoculated intratracheally with 104 P. aeruginosa mucoid PAO1 cells in agar beads. Three days following inoculation treatment was initiated. Animals were treated daily for 3 days with 100 µl of peptide solution (1 mg/ml) in 10 mM sodium citrate, which was deposited via either intratracheal instillation or aerosolization. Control animals received daily exposure to vehicle alone. At the end of the treatment the lungs of the animals were removed for quantitative culture. Four peptides, HBCM2, HBCM3, HBCP{alpha}-2, and HB71, demonstrated significant reduction in Pseudomonas bioburden in the lung of rats. Further in vivo studies provided direct evidence that anti-inflammatory activity was associated with three of these peptides. Therefore, small bioactive peptides have the potential to attack two of the components responsible for the progression of lung damage in the CF disease: infection and inflammation.

* Corresponding author. Mailing address: 22122 20th Ave. SE, Bothell, WA 98021. Phone: (425) 402-8400. Fax: (425) 806-2999. E-mail: lzhang{at}helixbiomedix.com.

Antimicrobial Agents and Chemotherapy, July 2005, p. 2921-2927, Vol. 49, No. 7
0066-4804/05/$08.00+0     doi:10.1128/AAC.49.7.2921-2927.2005
Copyright © 2005, American Society for Microbiology. All Rights Reserved.



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