A new hope for the peptide antibiotic ramoplanin — ASN Events
  1. Schedule
  2. Poster Session 2 - Wine Tasting
  3. A new hope for the peptide antibiotic ramoplanin

A new hope for the peptide antibiotic ramoplanin (#364)

Edward A. Marschall 1 2 , Rachel W. Cass 1 2 , Winfrey Hoo 1 2 , Alasdair I. McKay 2 , James D. Swarbrick 2 , Jennifer E. A. Payne 3 , Max J. Cryle 1 2 , Julien Tailhades 1 2
  1. Australian Research Council Centre of Excellence for Innovations in Peptide and Protein Science, Clayton, Victoria, Australia
  2. Monash University, Clayton, VIC, Australia
  3. Health & Biosecurity, CSIRO, Adelaide, South Australia, Australia

Antimicrobial resistance (AMR) is an extraordinary challenge in our society. In today’s context, a pool of potential antibiotics is waiting for a technological breakthrough to express their full potential. It is the case of the peptide antibiotic ramoplanin, which is active across all Gram-positive pathogens without a defined mechanism of resistance to date (1). Consequently, it is a well-suited molecule to join the arsenal to combat AMR pathogens if addressing its synthetic challenges and pharmacological properties.

By addressing a 20-year-old problem; namely arylglycine epimerization during solid-phase peptide synthesis (SPPS) (2), we have now identified a several strategies allowing the synthesis of challenging non-ribosomal peptides including precursors of glycopeptide antibiotics (3), an analogue of feglymycin (4) without compromising optical purity. We have exploited this protocol to synthesize several ramoplanin sequences in excellent yield (5-10%), which we have been extensively characterized by NMR (U-shaped structure) and antimicrobial activity assays (two clinical isolates). This method significantly reduces synthesis time (6-9 days) when compared with total syntheses (2-3 months) and enables drug discovery programs to include arylglycines in structure-activity relationship studies and drug development. 

64b0db1e671c5-IPS_Ab_Tailhades.jpg

 

  1. S. Walker, L. Chen, Y. Hu, Y. Rew, D. Shin and D. L. Boger, Chem. Rev., 2005, 105, 449-476.
  2. J. Tailhades, Int. J. Pept. Res. Therapeut., 2021, 28, 10.
  3. J. Tailhades, Y. Zhao, Y. T. C. Ho, A. Greule, I. Ahmed, M. Schoppet, K. Kulkarni, R. J. A. Goode, R. B. Schittenhelm, J. J. De Voss and M. J. Cryle, Angew. Chem. Int. Ed., 2020, 59, 10899-10903.
  4. F. Dettner, A. Hänchen, D. Schols, L. Toti, A. Nußer and R. D. Süssmuth, Angew. Chem. Int. Ed., 2009, 48, 1856-1861.
#AusPeptide2023