Synthesis and antibacterial activities of N-glycosylated derivatives of tyrocidine A, a macrocyclic peptide antibiotic.
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.
Hu
Honggang
H
Department of Chemistry, Wayne State University, Detroit, Michigan 48202, USA
Xue
Jie
J
Swarts
Benjamin M
BM
Wang
Qianli
Q
Wu
Qiuye
Q
Guo
Zhongwu
Z
D000900:Anti-Bacterial Agents / Q000138:chemical synthesis* / Q000494:pharmacology; D001412:Bacillus subtilis / Q000187:drug effects; D006020:Glycopeptides / Q000138:chemical synthesis* / Q000494:pharmacology; D006031:Glycosylation; D008826:Microbial Sensitivity Tests; D010456:Peptides, Cyclic / Q000138:chemical synthesis* / Q000494:pharmacology; D013329:Structure-Activity Relationship; D014440:Tyrocidine / Q000031:analogs & derivatives* / Q000138:chemical synthesis* / Q000494:pharmacology
D000900:Anti-Bacterial Agents; D006020:Glycopeptides; D010456:Peptides, Cyclic; D014440:Tyrocidine