A chemoenzymatic approach to glycopeptide antibiotics.
Many biologically active natural products are constrained by macrocyclization and modified with carbohydrates. These two types of modifications are essential for their biological activities. Here we report a chemoenzymatic approach to make carbohydrate-modified cyclic peptide antibiotics. Using a thioesterase domain from the decapeptide tyrocidine synthetase, 13 head-to-tail cyclized tyrocidine derivatives were obtained with one to three propargylglycines incorporated at positions 3-8. These cyclic peptides were then conjugated to 21 azido sugars via copper(I)-catalyzed cycloaddition. Antibacterial and hemolytic assays showed that the two best glycopeptides, Tyc4PG-14 and Tyc4PG-15, have a 6-fold better therapeutic index than the natural tyrocidine. We believe this method will also be useful for modifying other natural products to search for new therapeutics.
Lin
Hening
H
Department of Biological Chemistry and Molecular Pharmacology, Armenise 616, Harvard Medical School, Boston, Massachusetts 02115, USA.
Walsh
Christopher T
CT
D000480:Alkynes / Q000737:chemistry; D000595:Amino Acid Sequence; D000900:Anti-Bacterial Agents / Q000096:biosynthesis* / Q000138:chemical synthesis* / Q000494:pharmacology; D001386:Azides / Q000737:chemistry; D002241:Carbohydrates / Q000737:chemistry; D003500:Cyclization; D005998:Glycine / Q000031:analogs & derivatives* / Q000737:chemistry; D006020:Glycopeptides / Q000096:biosynthesis* / Q000138:chemical synthesis* / Q000494:pharmacology; D008826:Microbial Sensitivity Tests; D009005:Monosaccharides / Q000737:chemistry
D000480:Alkynes; D000900:Anti-Bacterial Agents; D001386:Azides; D002241:Carbohydrates; D006020:Glycopeptides; D009005:Monosaccharides; C009055:propargylglycine; D005998:Glycine