Poster Presentation 8th Modern Solid Phase Peptide Synthesis & Its Applications Symposium 2022

Chemo-enzymatic total synthesis of Vancomycin Analogues (#126)

Edward Marschall 1 , Julien Tailhades 1
  1. Monash University, Clayton, VIC, Australia

Glycopeptide antibiotics (especially vancomycin) are a clinically important family of antibiotics reserved for treating multidrug resistant bacteria1. The high complexity of the tricyclic molecule has made its development slow and hampered the success of these otherwise powerful compounds2. The use of enzymes in organic synthesis can be a powerful tool to help access complex molecules like vancomycin and aid in the development of new analogues3. Herein a bio-inspired approach of solid-phase peptide synthesis followed by the introduction of three sidechain-sidechain crosslinks using an enzymatic cascade is presented. This work shows that novel glycopeptide antibiotic analogues can be accessed rapidly via enzymatic catalysis.

  1. 1. Organization, W. H., Global priority list of antibiotic-resistant bacteria to guide research, discovery, and development of new antibiotics. Geneva: World Health Organization 2017.
  2. 2. Xie, J.; Pierce, J. G.; James, R. C.; Okano, A.; Boger, D. L., A Redesigned Vancomycin Engineered for Dual d-Ala-d-Ala and d-Ala-d-Lac Binding Exhibits Potent Antimicrobial Activity Against Vancomycin-Resistant Bacteria. Journal of the American Chemical Society 2011, 133 (35), 13946-13949.
  3. 3. Marschall, E.; Cryle, M. J.; Tailhades, J., Biological, chemical, and biochemical strategies for modifying glycopeptide antibiotics. Journal of Biological Chemistry 2019, 294 (49), 18769-18783.