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Antimicrobial Agents and Chemotherapy, December 2001, p. 3437-3444, Vol. 45, No. 12
0066-4804/01/$04.00+0   DOI: 10.1128/AAC.45.12.3437-3444.2001
Copyright © 2001, American Society for Microbiology. All rights reserved.

P-113D, an Antimicrobial Peptide Active against Pseudomonas aeruginosa, Retains Activity in the Presence of Sputum from Cystic Fibrosis Patients

Umadevi S. Sajjan,1 Linh T. Tran,2 Nuria Sole,2,dagger Christopher Rovaldi,2,Dagger Alan Akiyama,2,§ Phillip M. Friden,2,|| Janet F. Forstner,1 and David M. Rothstein2,*

The Hospital for Sick Children, Toronto, Ontario, Canada,1 and Periodontix, Inc., Watertown, Massachusetts2

Received 1 May 2001/Returned for modification 13 August 2001/Accepted 12 September 2001

Antimicrobial peptides are a source of novel agents that could be useful for treatment of the chronic lung infections that afflict cystic fibrosis (CF) patients. Efficacy depends on antimicrobial activity against the major pathogens of CF patients, Pseudomonas aeruginosa, Staphylococcus aureus, and Haemophilus influenzae, in the environment of the CF patient's airway. We describe the in vitro efficacies of derivatives of histatins, which are histidine-rich peptides produced by the salivary glands of humans and higher primates. P-113, a peptide containing 12 of the 24 amino acid residues of the parent molecule, histatin 5, retained full antibacterial activity and had a good spectrum of activity in vitro against the prominent pathogens of CF patients. However, P-113 was not active in the presence of purulent sputum from CF patients. In contrast, P-113D, the mirror-image peptide with the amino acid residues in the D configuration, was stable in sputum, was as active as P-113 against pathogens of CF patients in the absence of sputum and retained significant activity in the presence of sputum from CF patients. Recombinant human DNase, which effectively liquefies sputum, enhanced the activity of P-113D in undiluted sputum against both exogenous (added) bacteria and endogenous bacteria. Because of its properties, P-113D shows potential as an inhalant in chronic suppressive therapy for CF patients.

* Corresponding author. Present address: Demegen, Inc., 313 Pleasant St., Watertown, MA 02472. Phone: (617) 926-1980, ext. 236. Fax: (617) 926-4776. E-mail: drothstein{at}demegen.com.

dagger Present address: Avecia, Inc., Milford, Mass.

Dagger Present address: Cubist Pharmaceuticals, Cambridge, Mass.

§ Present address: Praecis, Cambridge, Mass.

|| Present address: Demegen, Inc., Watertown, Mass.

Antimicrobial Agents and Chemotherapy, December 2001, p. 3437-3444, Vol. 45, No. 12
0066-4804/01/$04.00+0   DOI: 10.1128/AAC.45.12.3437-3444.2001
Copyright © 2001, American Society for Microbiology. All rights reserved.


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