title: Synthesis and biological evaluation of vancomycin dimers with potent activity against vancomycin-resistant bacteria: target-accelerated combinatorial synthesis.
abstract: Based on the notion that dimerization and/or variation of amino acid 1 of vancomycin could potentially enhance biological activity, a series of synthetic and chemical biology studies were undertaken in order to discover potent antibacterial agents. Herein we describe two ligation methods (disulfide formation and olefin metathesis) for dimerizing vancomycin derivatives and applications of target-accelerated combinatorial synthesis (e.g. combinatorial synthesis in the presence of vancomycin's target Ac2-L-Lys-D-Ala-D-Ala) to generate libraries of vancomycin dimers. Screening of these compound libraries led to the identification of a number of highly potent antibiotics effective against vancomycin-suspectible, vancomycin-intermediate resistant and, most significantly, vancomycin-resistant bacteria.
authors.affiliation: Department of Chemistry, and The Skaggs Institute for Chemical Biology, The Scripps Research Institute, La Jolla 92037, USA.
authors.forename: K C
authors.initials: KC
authors.lastname: Nicolaou
authors.forename: R
authors.initials: R
authors.lastname: Hughes
authors.forename: S Y
authors.initials: SY
authors.lastname: Cho
authors.forename: N
authors.initials: N
authors.lastname: Winssinger
authors.forename: H
authors.initials: H
authors.lastname: Labischinski
authors.forename: R
authors.initials: R
authors.lastname: Endermann
mesh_terms: D000900:Anti-Bacterial Agents / Q000138:chemical synthesis* / Q000494:pharmacology; D020650:Combinatorial Chemistry Techniques / Q000379:methods*; D003432:Cross-Linking Reagents / Q000737:chemistry; D019281:Dimerization; D004351:Drug Resistance; D016984:Enterococcus faecium / Q000187:drug effects; D006095:Gram-Positive Cocci / Q000187:drug effects; D008826:Microbial Sensitivity Tests; D019151:Peptide Library; D013211:Staphylococcus aureus / Q000187:drug effects; D013296:Streptococcus pneumoniae / Q000187:drug effects; D013329:Structure-Activity Relationship; D014640:Vancomycin / Q000031:analogs & derivatives* / Q000138:chemical synthesis / Q000494:pharmacology
chemical_list: D000900:Anti-Bacterial Agents; D003432:Cross-Linking Reagents; D019151:Peptide Library; D014640:Vancomycin