A Chemoenzymatic Approach to the Synthesis of Glycopeptide Antibiotic Analogues. (11th May 2020)

• Record Type: Journal Article
• Authors: Tailhades, Julien; Zhao, Yongwei; Ho, Y. T. Candace; Greule, Anja; Ahmed, Iftekhar; Schoppet, Melanie; Kulkarni, Ketav; Goode, Rob J. A.; Schittenhelm, Ralf B.; De Voss, James J.; Cryle, Max J.
• Is Part Of: Angewandte Chemie. Volume 132:Number 27(2020)
• Page Start: 10991
• Page End: 10995
• Publication Date: 2020-05-11
• Subjects: biocatalysis -- biosynthesis -- nonribosomal peptides -- cytochrome P450 enzymes -- glycopeptide antibiotics; Chemistry -- Periodicals; 540
• DOI: 10.1002/ange.202003726
• Languages: English
• ISSNs: 0044-8249

Abstract

Abstract: 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 since the selectivity of the biosynthetic crosslinking enzymes for altered substrates is largely unknown. We show that combining 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 identified peptide modifications that are enzymatically tolerated and can also reveal the mechanistic basis for substrate intolerance where present. Using this approach, we next specifically activated modified residues within GPAs for functionalisation at previously inaccessible positions, thereby offering the possibility of late‐stage chemical functionalisation after GPA cyclisation is complete. Abstract : Biosynthesis remains the only effective means to produce the complex cross‐linked structures of glycopeptide antibiotics (GPAs). Investigation of the final crosslinking steps of the biosynthesis in vitro showed that the enzymes responsible for these challenging transformations possess broad substrate tolerance. Furthermore, incompatible substrates can be substituted with alkyne‐functionalized peptides for late‐stage modification through click chemistry.