title: D-enantiomeric peptides that eradicate wild-type and multidrug-resistant biofilms and protect against lethal Pseudomonas aeruginosa infections.
abstract: In many infections, bacteria form surface-associated communities known as biofilms that are substantially more resistant to antibiotics than their planktonic counterparts. Based on the design features of active antibiofilm peptides, we made a series of related 12-amino acid L-, D- and retro-inverso derivatives. Specific D-enantiomeric peptides were the most potent at inhibiting biofilm development and eradicating preformed biofilms of seven species of wild-type and multiply antibiotic-resistant Gram-negative pathogens. Moreover, these peptides showed strong synergy with conventional antibiotics, reducing the antibiotic concentrations required for complete biofilm inhibition by up to 64-fold. As shown previously for 1018, these D-amino acid peptides targeted the intracellular stringent response signal (p)ppGpp. The most potent peptides DJK-5 and DJK-6 protected invertebrates from lethal Pseudomonas aeruginosa infections and were considerably more active than a previously described L-amino acid peptide 1018. Thus, the protease-resistant peptides produced here were more effective both in vitro and in vivo.
authors.affiliation: Department of Microbiology and Immunology, Centre for Microbial Diseases and Immunity Research, University of British Columbia, Vancouver, BC V6T 1Z4, Canada.
authors.forename: César
authors.initials: C
authors.lastname: de la Fuente-Núñez
authors.affiliation: Department of Microbiology and Immunology, Centre for Microbial Diseases and Immunity Research, University of British Columbia, Vancouver, BC V6T 1Z4, Canada.
authors.forename: Fany
authors.initials: F
authors.lastname: Reffuveille
authors.affiliation: Department of Microbiology and Immunology, Centre for Microbial Diseases and Immunity Research, University of British Columbia, Vancouver, BC V6T 1Z4, Canada.
authors.forename: Sarah C
authors.initials: SC
authors.lastname: Mansour
authors.affiliation: Faculty of Science and Technology, Athabasca University, Athabasca, AB T9S 3A3, Canada.
authors.forename: Shauna L
authors.initials: SL
authors.lastname: Reckseidler-Zenteno
authors.affiliation: Faculty of Science and Technology, Athabasca University, Athabasca, AB T9S 3A3, Canada.
authors.forename: Diego
authors.initials: D
authors.lastname: Hernández
authors.affiliation: Laboratory of Pharmaceutical Microbiology, Ghent University, Harelbekestraat 72, 9000 Ghent, Belgium.
authors.forename: Gilles
authors.initials: G
authors.lastname: Brackman
authors.affiliation: Laboratory of Pharmaceutical Microbiology, Ghent University, Harelbekestraat 72, 9000 Ghent, Belgium.
authors.forename: Tom
authors.initials: T
authors.lastname: Coenye
authors.affiliation: Department of Microbiology and Immunology, Centre for Microbial Diseases and Immunity Research, University of British Columbia, Vancouver, BC V6T 1Z4, Canada. Electronic address: bob@hancocklab.com.
authors.forename: Robert E W
authors.initials: RE
authors.lastname: Hancock
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D000890:Anti-Infective Agents / Q000737:chemistry* / Q000494:pharmacology / Q000627:therapeutic use; D018441:Biofilms / Q000187:drug effects; D017173:Caenorhabditis elegans / Q000187:drug effects; D024881:Drug Resistance, Bacterial / Q000187:drug effects; D008826:Microbial Sensitivity Tests; D009842:Oligopeptides / Q000737:chemistry* / Q000494:pharmacology / Q000627:therapeutic use; D010455:Peptides / Q000737:chemistry* / Q000494:pharmacology / Q000627:therapeutic use; D011552:Pseudomonas Infections / Q000517:prevention & control / Q000662:veterinary; D011550:Pseudomonas aeruginosa / Q000502:physiology*; D013237:Stereoisomerism
chemical_list: D000890:Anti-Infective Agents; C000602801:DJK-5 peptide; C000602802:DJK-6 peptide; D009842:Oligopeptides; D010455:Peptides