title: Synthesis and antibacterial activity of amphiphilic lysine-ligated neomycin B conjugates.
abstract: Amphiphilic lysine-ligated neomycin B building blocks were prepared by reductive amination of a protected C5″-modified neomycin B-based aldehyde and side chain-unprotected lysine or lysine-containing peptides. It was demonstrated that a suitably protected lysine-ligated neomycin B conjugate (NeoK) serves as a building block for peptide synthesis, enabling incorporation of aminoglycoside binding sites into peptides. Antibacterial testing of three amphiphilic lysine-ligated neomycin B conjugates against a representative panel of Gram-positive and Gram-negative strains demonstrates that C5″-modified neomycin-lysine conjugate retains antibacterial activity. However, in most cases the lysine-ligated neomycin B analogs display reduced potency against Gram-positive strains when compared to unmodified neomycin B or unligated peptide. An exception is MRSA where an eightfold enhancement was observed. When compared to unmodified neomycin B, the prepared lysine-neomycin conjugates exhibited a 4-8-fold enhanced Gram-negative activity against Pseudomonas aeruginosa and up to 12-fold enhanced activity was observed when compared to unligated reference peptides.
authors.affiliation: Department of Chemistry, University of Manitoba, Winnipeg, Manitoba, Canada R3T 2N2.
authors.forename: Smritilekha
authors.initials: S
authors.lastname: Bera
authors.forename: George G
authors.initials: GG
authors.lastname: Zhanel
authors.forename: Frank
authors.initials: F
authors.lastname: Schweizer
mesh_terms: D000617:Aminoglycosides / Q000737:chemistry*; D000900:Anti-Bacterial Agents / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D005601:Framycetin / Q000031:analogs & derivatives / Q000097:blood*; D008239:Lysine / Q000737:chemistry*; D009682:Magnetic Resonance Spectroscopy; D008826:Microbial Sensitivity Tests; D015394:Molecular Structure; D010455:Peptides / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D011550:Pseudomonas aeruginosa / Q000187:drug effects
chemical_list: D000617:Aminoglycosides; D000900:Anti-Bacterial Agents; D010455:Peptides; D005601:Framycetin; D008239:Lysine