Solid- and solution-phase synthesis of vancomycin and vancomycin analogues with activity against vancomycin-resistant bacteria.
Vancomycin, the prototypical member of the glycopeptide family of antibiotics, is a clinically used antibiotic employed against a variety of drug-resistant bacterial strains including methicillin-resistant Staphylococcus aureus (MRSA). The recent emergence of vancomycin resistance, viewed as a growing threat to public health, prompted us to initiate a program aimed at restoring the potency of this important antibiotic through chemical manipulation of the vancomycin structure. Herein, we describe the development of synthetic technology based on the design of a novel selenium safety catch linker, application of this technology to a solid-phase semisynthesis of vancomycin, and the solid- and solution-phase synthesis of vancomycin libraries. Biological evaluation of these compound libraries led to the identification of a number of in vitro highly potent antibacterial agents effective against vancomycin-resistant bacteria. In addition to aiding these investigations, the solid-phase chemistry described herein is expected to enhance the power of combinatorial chemistry and facilitate chemical biology and medicinal chemistry studies.
Nicolaou
K C
KC
Department of Chemistry and The Skaggs Institute for Chemical Biology, La Jolla, California 92037, USA. kcn@scripps.edu
Cho
S Y
SY
Hughes
R
R
Winssinger
N
N
Smethurst
C
C
Labischinski
H
H
Endermann
R
R
D000900:Anti-Bacterial Agents / Q000138:chemical synthesis* / Q000494:pharmacology; D020650:Combinatorial Chemistry Techniques / Q000379:methods*; 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; D019151:Peptide Library; D014640:Vancomycin