title: Evaluation of the antibacterial and antibiofilm activities of novel CRAMP-vancomycin conjugates with diverse linkers.
abstract: We report the design, synthesis and antibacterial activity analysis of conjugates of vancomycin and cathelicidin-related antimicrobial peptides (CRAMP). Vancomycin inhibits the nascent peptidoglycan synthesis and is highly active against Gram-positive bacteria, whereas Gram-negative bacteria are generally insensitive due to a protective outer membrane. CRAMP is known to translocate across the Gram-negative outer membrane by a self-promoted uptake mechanism. Vancomycin-CRAMP conjugates were synthesized using click chemistry with diverse hydrophilic and hydrophobic linkers, with CRAMP functioning as a carrier peptide for the transfer of vancomycin through the outer membrane. Small hydrophobic linkers with an aromatic group result in the most active conjugates against planktonic Gram-negative bacteria, while maintaining the high activity of vancomycin against Gram-positive bacteria. These conjugates thus show a broad-spectrum activity, which is absent in CRAMP or vancomycin alone, and which is strongly improved compared to an equimolar mixture of CRAMP and vancomycin. In addition, these conjugates also show a strong inhibitory activity against S. Typhimurium biofilm formation.
authors.affiliation: Laboratory for Organic & Microwave-Assisted Chemistry (LOMAC), Department of Chemistry, KU Leuven, Celestijnenlaan 200F, B-3001 Leuven, Belgium. Erik.VanderEycken@chem.kuleuven.be.
authors.forename: Nigam M
authors.initials: NM
authors.lastname: Mishra
authors.forename: Yves
authors.initials: Y
authors.lastname: Briers
authors.forename: Chris
authors.initials: C
authors.lastname: Lamberigts
authors.forename: Hans
authors.initials: H
authors.lastname: Steenackers
authors.forename: Stijn
authors.initials: S
authors.lastname: Robijns
authors.forename: Bart
authors.initials: B
authors.lastname: Landuyt
authors.forename: Jos
authors.initials: J
authors.lastname: Vanderleyden
authors.forename: Liliane
authors.initials: L
authors.lastname: Schoofs
authors.forename: Rob
authors.initials: R
authors.lastname: Lavigne
authors.forename: Walter
authors.initials: W
authors.lastname: Luyten
authors.forename: Erik V
authors.initials: EV
authors.lastname: Van der Eycken
mesh_terms: D000595:Amino Acid Sequence; D000900:Anti-Bacterial Agents / Q000737:chemistry / Q000494:pharmacology*; D023181:Antimicrobial Cationic Peptides; D001419:Bacteria / Q000187:drug effects / Q000254:growth & development; D018441:Biofilms / Q000187:drug effects* / Q000254:growth & development; D054804:Cathelicidins / Q000737:chemistry / Q000494:pharmacology*; D002853:Chromatography, Liquid; D057927:Hydrophobic and Hydrophilic Interactions; D007536:Isomerism; D013058:Mass Spectrometry; D008826:Microbial Sensitivity Tests; D018625:Microscopy, Atomic Force; D008969:Molecular Sequence Data; D014640:Vancomycin / Q000737:chemistry / Q000494:pharmacology*
chemical_list: D000900:Anti-Bacterial Agents; D023181:Antimicrobial Cationic Peptides; D054804:Cathelicidins; D014640:Vancomycin