title: Characterization of a proteolytically stable multifunctional host defense peptidomimetic.
abstract: The in vitro activity of a host defense peptidomimetic (HDM-4) was investigated. The compound exhibited an antimicrobial activity profile against a range of Gram-negative bacteria. HDM-4 permeabilized the outer membrane and partly depolarized the inner membrane at its minimal inhibitory concentration (MIC). Moreover, it was demonstrated that HDM-4 was distributed widely in the bacterial cell at lethal concentrations, and that it could bind to DNA. It was confirmed that the multimodal action of HDM-4 resulted in it being less likely to lead to resistance development as compared to single-target antibiotics. HDM-4 exhibited multispecies anti-biofilm activity at sub-MIC levels. Furthermore, HDM-4 modulated the immune response by inducing the release of the chemoattractants interleukin-8 (IL-8), monocyte chemotactic protein-1 (MCP-1), and MCP-3 from human peripheral blood mononuclear cells. In addition, the compound suppressed lipopolysaccharide-mediated inflammation by reducing the release of the pro-inflammatory cytokines IL-6 and tumor necrosis factor-α.
authors.affiliation: Department of Drug Design and Pharmacology, Faculty of Health and Medical Sciences, University of Copenhagen, Universitetsparken 2, Copenhagen DK-2100, Denmark; Centre for Microbial Diseases and Immunity Research, University of British Columbia, 2259 Lower Mall Research Station, Vancouver, BC V6T 1Z4, Canada.
authors.forename: Rasmus D
authors.initials: RD
authors.lastname: Jahnsen
authors.forename: Evan F
authors.initials: EF
authors.lastname: Haney
authors.forename: Henrik
authors.initials: H
authors.lastname: Franzyk
authors.forename: Robert E W
authors.initials: RE
authors.lastname: Hancock
mesh_terms: D000890:Anti-Infective Agents / Q000378:metabolism* / Q000494:pharmacology*; D018441:Biofilms / Q000187:drug effects; D002462:Cell Membrane / Q000187:drug effects / Q000378:metabolism; D004247:DNA / Q000378:metabolism; D019453:Escherichia coli O157 / Q000187:drug effects / Q000502:physiology; D006801:Humans; D056747:Immunomodulation / Q000187:drug effects; D007249:Inflammation / Q000139:chemically induced / Q000276:immunology; D007700:Kinetics; D008070:Lipopolysaccharides / Q000494:pharmacology; D057786:Peptidomimetics / Q000378:metabolism* / Q000494:pharmacology*; D055550:Protein Stability; D059748:Proteolysis
chemical_list: D000890:Anti-Infective Agents; D008070:Lipopolysaccharides; D057786:Peptidomimetics; D004247:DNA