Synthesis and Antibacterial Activities of N-Glycosylated Derivatives of Tyrocidine A, a Macrocyclic Peptide Antibiotic

Honggang Hu, Benjamin Swarts

Research output: Contribution to journalArticlepeer-review

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.
Original languageEnglish
Pages (from-to)2052--2059
JournalJ. Med. Chem.
Volume52
Issue number7
StatePublished - 2009

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