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Systemic antibacterial activity of novel synthetic cyclic peptides.

Dartois, Veronique and Sanchez-Quesada, Jorge and Cabezas, Edelmira and Chi, Ellen and Dubbelde, Chad and Dunn, Carrie and Granja, Juan and Gritzen, Colleen and Weinberger, Dana and Ghadiri, M Reza and Parr, Thomas R (2005) Systemic antibacterial activity of novel synthetic cyclic peptides. Antimicrobial Agents and Chemotherapy, 49 (8). pp. 3302-3310. ISSN 0066-4804

Abstract

Cyclic peptides with an even number of alternating d,l-alpha-amino acid residues are known to self-assemble into organic nanotubes. Such peptides previously have been shown to be stable upon protease treatment, membrane active, and bactericidal and to exert antimicrobial activity against Staphylococcus aureus and other gram-positive bacteria. The present report describes the in vitro and in vivo pharmacology of selected members of this cyclic peptide family. The intravenous (i.v.) efficacy of six compounds with MICs of less than 12 microg/ml was tested in peritonitis and neutropenic-mouse thigh infection models. Four of the six peptides were efficacious in vivo, with 50% effective doses in the peritonitis model ranging between 4.0 and 6.7 mg/kg against methicillin-sensitive S. aureus (MSSA). In the thigh infection model, the four peptides reduced the bacterial load 2.1 to 3.0 log units following administration of an 8-mg/kg i.v. dose. Activity against methicillin-resistant S. aureus was similar to MSSA. The murine pharmacokinetic profile of each compound was determined following i.v. bolus injection. Interestingly, those compounds with poor efficacy in vivo displayed a significantly lower maximum concentration of the drug in serum and a higher volume of distribution at steady state than compounds with good therapeutic properties. S. aureus was unable to easily develop spontaneous resistance upon prolonged exposure to the peptides at sublethal concentrations, in agreement with the proposed interaction with multiple components of the bacterial membrane canopy. Although additional structure-activity relationship studies are required to improve the therapeutic window of this class of antimicrobial peptides, our results suggest that these amphipathic cyclic d,l-alpha-peptides have potential for systemic administration and treatment of otherwise antibiotic-resistant infections.

Item Type: Article
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Additional Information: free final full text version available at publisher's official URL and at PubMedCentral; author can archive post-print (ie final draft post-refereeing); but on personal or university-hosted websites only
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Date Deposited: 14 Dec 2009 14:01
Last Modified: 31 Jan 2013 01:20
URI: https://oak.novartis.com/id/eprint/312

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