Synthesis and antibacterial activities of N-glycosylated derivatives of tyrocidine A, a macrocyclic peptide antibiotic

J Med Chem. 2009 Apr 9;52(7):2052-9. doi: 10.1021/jm801577r.

Abstract

An efficient and practical method for macrocyclic glycopeptide synthesis was developed and utilized to synthesize tyrocidine A and its glycosylated derivatives. The method is based on solid-phase peptide synthesis using 2-chlorotrityl resin as the solid-phase support and glycosyl amino acids as building blocks. After glycopeptides with fully protected glycans and side chains were released from the acid-labile resin, their C- and N-termini were intramolecularly coupled in solution to afford cyclic glycopeptides in quantitative yields. This synthetic method should be generally applicable to various macrocyclic glycopeptides. Biological studies of the synthetic tyrocidine A derivatives showed that linking glycans directly to the Asn residue of tyrocidine A diminished its antibacterial activity, but linking glycans to Asn via a simple spacer did not. These results revealed the important impact of glycans on the activities, and probably the structures, of glycopeptide antibiotics.

Publication types

  • Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

  • Anti-Bacterial Agents / chemical synthesis*
  • Anti-Bacterial Agents / pharmacology
  • Bacillus subtilis / drug effects
  • Glycopeptides / chemical synthesis*
  • Glycopeptides / pharmacology
  • Glycosylation
  • Microbial Sensitivity Tests
  • Peptides, Cyclic / chemical synthesis*
  • Peptides, Cyclic / pharmacology
  • Structure-Activity Relationship
  • Tyrocidine / analogs & derivatives*
  • Tyrocidine / chemical synthesis*
  • Tyrocidine / pharmacology

Substances

  • Anti-Bacterial Agents
  • Glycopeptides
  • Peptides, Cyclic
  • Tyrocidine