Oral Presentation 9th Modern Solid Phase Peptide Synthesis & Its Applications Symposium 2023

A new hope for the peptide antibiotic ramoplanin (98356)

Edward A. Marschall 1 2 , Rachel W Cass 1 2 , Komal M Prasad 1 2 , James Swarbrick 1 , Alasdair I. McKay 1 , Jennifer A. E. Payne 3 , Max J. Cryle 1 2 , Julien Tailhades 1 2
  1. Monash University, Clayton, VIC, Australia
  2. Australian Research Council Centre of Excellence for Innovations in Peptide and Protein Science, Clayton, Victoria, 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 several SPPS strategies allowing the synthesis of challenging non-ribosomal peptides including precursors of glycopeptide antibiotics (3) or an analogue of feglymycin (4). The key is a short exposure to an organic basis (eg. DBU, piperidine) for the Fmoc removal step and avoiding the usage of a small nucleophilic basis (eg. Hydrazine) in the synthesis process. We have exploited this protocol to synthesize several ramoplanin sequences in excellent yield (3-10%), which we have extensively characterized by NMR (U-shaped structure) and antimicrobial activity assays (3 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.

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