Systemic Antibacterial Activity of Novel Synthetic Cyclic Peptides

Abstract

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 g/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.The incidence of community-acquired and nosocomially acquired infections due to the bacterium Staphylococcus aureus is rising (25). From 1990 to 1992, this microorganism was the most common cause of nosocomial pneumonias and surgical wound infections (14). The overall growing crisis in antibiotic resistance and the rise in the incidence of methicillin-resistant S. aureus (MRSA) strains (32, 33) have emphasized the need for therapeutic alternatives to currently available antibiotics. Vancomycin remains the mainstay of therapy against several resistant gram-positive pathogens. However, vancomycin is slowly bactericidal, and with the recent increase in nosocomial infections caused by vancomycin-resistant enterococci and S. aureus (4, 13, 16), there is a growing need for antimicrobial agents with novel mechanisms of action to attack these resistant pathogens. The Food and Drug Administration recently approved the use of daptomycin, a cyclic lipodepsipeptide antibiotic, for the treatment of complicated skin and skin structure infections caused by several gram-positive bacteria. Its mode of action seems to be related to the disruption of the membrane potential of ...

Efficacy of OH-CATH30 and Its Analogs against Drug-Resistant Bacteria In Vitro and in Mouse Models

“…ICR mice were rendered neutropenic by an i.p. injection of 150 and 100 mg/kg of body weight cyclophosphamide on days 0 and 3, respectively, and infection was induced on day 4 (11). The left thighs of mice were injected with E. coli 25922 (approximately 5 ϫ 10 5 CFU/thigh) prepared as described above.…”

Self-assembled peptide nanomaterials for biomedical applications: promises and pitfalls

“…94 In previous studies, cyclic peptide nanotubes were mainly used for antibacterial applications. 45,95,96 With stacking peptide cycles, nanotubes are able to form transmembrane pores to mimic ion channels in membranes. 45,97,98 Mechanistic studies showed that the antibacterial activity is due to the enhancement of the membrane permeability.…”

“…45,97,98 Mechanistic studies showed that the antibacterial activity is due to the enhancement of the membrane permeability. 96,97 Moreover, these cyclic peptides could also inhibit virus infections by blocking virus entry or endosome escape in mammalian cells. To inhibit methicillin-resistant bacteria, it is significant to choose a specific peptide sequence against bacterial selectively rather than mammalian cells.…”

Fungal cyclooligomerdepsipeptides: From classical biochemistry to combinatorial biosynthesis

“…Beauvericin (1), enniatins (2), bassianolide (3) and PF1022A (4) and its congeners contain residues with alternating D and L configuration, similar to 6-8-member cyclic D,L-a-peptide antibacterial agents. 10,11 Variations in the amino acid or the hydroxycarboxylic acid positions of the monomers lead to the production of various COD congeners in a given COD producer fungus. COD production in fungi has hitherto been only documented in the Hypocreomycetidae and the Xylariomycetidae, two subclasses of the Sordariomycetes.…”