title: Systemic antibacterial activity of novel synthetic cyclic peptides.
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.
authors.affiliation: Novartis Institute for Tropical Diseases, 10 Biopolis Rd., #05-01 Chromos, Singapore 138670. veronique.dartois@novartis.com
authors.forename: Véronique
authors.initials: V
authors.lastname: Dartois
authors.forename: Jorge
authors.initials: J
authors.lastname: Sanchez-Quesada
authors.forename: Edelmira
authors.initials: E
authors.lastname: Cabezas
authors.forename: Ellen
authors.initials: E
authors.lastname: Chi
authors.forename: Chad
authors.initials: C
authors.lastname: Dubbelde
authors.forename: Carrie
authors.initials: C
authors.lastname: Dunn
authors.forename: Juan
authors.initials: J
authors.lastname: Granja
authors.forename: Colleen
authors.initials: C
authors.lastname: Gritzen
authors.forename: Dana
authors.initials: D
authors.lastname: Weinberger
authors.forename: M Reza
authors.initials: MR
authors.lastname: Ghadiri
authors.forename: Thomas R
authors.initials: TR
authors.lastname: Parr
mesh_terms: D000818:Animals; D000900:Anti-Bacterial Agents / Q000138:chemical synthesis / Q000493:pharmacokinetics / Q000494:pharmacology / Q000627:therapeutic use; D005260:Female; D051379:Mice; D008813:Mice, Inbred ICR; D008826:Microbial Sensitivity Tests; D009135:Muscular Diseases / Q000188:drug therapy* / Q000382:microbiology; D009503:Neutropenia / Q000139:chemically induced; D019151:Peptide Library; D010456:Peptides, Cyclic / Q000138:chemical synthesis / Q000493:pharmacokinetics / Q000494:pharmacology / Q000627:therapeutic use; D010538:Peritonitis / Q000188:drug therapy* / Q000382:microbiology; D013203:Staphylococcal Infections / Q000188:drug therapy* / Q000382:microbiology; D013211:Staphylococcus aureus / Q000187:drug effects; D013848:Thigh / Q000382:microbiology; D016896:Treatment Outcome
chemical_list: D000900:Anti-Bacterial Agents; D019151:Peptide Library; D010456:Peptides, Cyclic