Synthesis and biological evaluation of vancomycin dimers with potent activity against vancomycin-resistant bacteria: target-accelerated combinatorial synthesis.
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.
Nicolaou
K C
KC
Department of Chemistry, and The Skaggs Institute for Chemical Biology, The Scripps Research Institute, La Jolla 92037, USA.
Hughes
R
R
Cho
S Y
SY
Winssinger
N
N
Labischinski
H
H
Endermann
R
R
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
D000900:Anti-Bacterial Agents; D003432:Cross-Linking Reagents; D019151:Peptide Library; D014640:Vancomycin