A chemoenzymatic approach to the synthesis of glycopeptide antibiotic analogues

Abstract: The glycopeptide antibiotics (GPAs) are important antibiotics that are highly challenging to synthesise due to their unique and heavily crosslinked structure. Given this, the synthetic production and diversification of this key compound class remains impractical.  Furthermore, the possibility of biosynthetic reengineering of GPAs is not yet feasible as the selectivity of the biosynthetic crosslinking enzymes for altered substrates is largely unknown. Here, we show that the combination of peptide synthesis with enzymatic cyclisation enables the formation of novel examples of GPAs and provides an indication of the utility of these crucial enzymes. By accessing the biosynthetic process in vitro, we identify peptide modifications that are

enzymatically tolerated and can also reveal the mechanistic basis for substrate intolerance where present. Using this approach, we next specifically activate modified residues within GPAs for functionalisation at previously inaccessible positions, offering the possibility of late-stage chemical functionalisation after GPA cyclisation is complete.