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Antimicrobial Agents and Chemotherapy, August 2005, p. 3302-3310, Vol. 49, No. 8
0066-4804/05/$08.00+0     doi:10.1128/AAC.49.8.3302-3310.2005
Copyright © 2005, American Society for Microbiology. All Rights Reserved.

Systemic Antibacterial Activity of Novel Synthetic Cyclic Peptides

Véronique Dartois,^1,* Jorge Sanchez-Quesada,^1,, Edelmira Cabezas,¹ Ellen Chi,¹ Chad Dubbelde,¹ Carrie Dunn,¹ Juan Granja,^1, Colleen Gritzen,¹ Dana Weinberger,¹ M. Reza Ghadiri,² and Thomas R. Parr Jr.^1,¶

Adaptive Therapeutics, Inc., 5820 Nancy Ridge Drive, San Diego, California 92121,¹ The Scripps Research Institute, La Jolla, California 92037²

Received 8 February 2005/ Returned for modification 18 March 2005/ Accepted 16 May 2005

Cyclic peptides with an even number of alternating D,L--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 µg/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--peptides have potential for systemic administration and treatment of otherwise antibiotic-resistant infections.

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* Corresponding author. Mailing address: Novartis Institute for Tropical Diseases, 10 Biopolis Rd., #05-01 Chromos, Singapore 138670. Phone: 65 6722 2930. Fax: 65 6722 2910. E-mail: veronique.dartois{at}novartis.com.

V.D. and J.S.-Q. contributed equally to the present study.

Present address: Departamento de Química Orgánica, Universidad Autónoma de Madrid, Cantoblanco, 1049 Madrid, Spain.

Present address: Departamento de Química Orgánica, Facultad de Química, Universidad de Santiago, E-15782 Santiago de Compostela, Spain.

^¶ Present address: Targanta Therapeutics Inc., 7170 Frederick Banting, St. Laurent H4S 2A1, Quebec, Canada.

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Antimicrobial Agents and Chemotherapy, August 2005, p. 3302-3310, Vol. 49, No. 8
0066-4804/05/$08.00+0     doi:10.1128/AAC.49.8.3302-3310.2005
Copyright © 2005, American Society for Microbiology. All Rights Reserved.

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