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Journal of Antimicrobial Chemotherapy (2002) 50, 339-348
© 2002 The British Society for Antimicrobial Chemotherapy

Analysis of the cytotoxicity of synthetic antimicrobial peptides on mouse leucocytes: implications for systemic use

Sabrina Pacor1,*, Anna Giangaspero2, Marina Bacac1, Gianni Sava1 and Alessandro Tossi2

Departments of 1 Biomedical Sciences and 2 Biochemistry, Biophysics and Macromolecular Chemistry, University of Trieste, Trieste I-34127, Italy

Received 12 February 2002; returned 5 May 2002; revised 28 May 2002; accepted 10 June 2002

We have analysed the toxicity of highly cationic, artificial {alpha}-helical antimicrobial peptides on blood cells to assess their suitability for systemic application. Flow cytometric methods, based on the uptake of propidium iodide, were used to obtain a rapid and quantitative estimate of membrane damage to resting and concanavalin A-activated mouse lymphocytes, which was further confirmed by morphological changes as observed by scanning electron microscopy. Membrane permeabilization appeared to correlate with structural characteristics, so that the peptide L-19(9/B), which contains helix-stabilizing aminoisobutyric acid (Aib) residues and is a potent antimicrobial, was also the most lytic towards both mouse lymphocytes and human erythrocytes. Reducing the propensity for helix formation in P19(8) resulted in a marked reduction in in vitro cytotoxicity. Changing the helical sense in D-P19(9/B) also resulted in a significant decrease in cytolytic activity towards both erythrocytes and leucocytes. A limited assessment in BALB/c mice confirmed a lower in vivo toxicity of P19(8) than L-P19(9/B). In a study of the systemic antimycotic activity of P19(8) in a mouse protection model, a modest prolongation in survival of Candida albicans-infected animals after intravenous administration was observed at 5 mg/kg peptide but not at higher doses. The implications of these observations for the systemic use of this type of peptide are discussed.

* Corresponding author. Tel: +39-040-5583529; Fax: +39-40-577435; E-mail: pacorsab{at}units.it


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