Glycopeptide Antibiotic Biosynthesis and Natural Product Chemistry

Glycopeptide antibiotics are a class of nonribosomal peptides renowned for their complex crosslinked heptapeptide cores, extensive glycosylation and halogenation patterns. They are assembled by modular nonribosomal peptide synthetases (NRPSs) that select and activate unusual amino acids, including 4-hydroxyphenylglycine and beta-hydroxytyrosine, before cyclisation and tailoring. A cascade of cytochrome P450 (Oxy) enzymes catalyses oxidative phenol coupling to install three or more aryl–aryl and aryl–ether crosslinks, shaping the rigid aglycone scaffold essential for high-affinity binding to bacterial cell-wall precursors. Subsequent enzymatic glycosylation and halogenation diversify activity spectra and pharmacokinetic properties. Advances in bioinformatics and structural biology have illuminated enzyme–carrier interactions, substrate scope and modular reprogramming, offering routes to novel analogues. Natural product chemists strive to combine total chemical synthesis, chemoenzymatic methods and in vivo strain engineering to overcome limitations of fermentation yields and to address the urgent threat of resistant pathogens. The global significance of glycopeptide antibiotics extends from last-line therapeutics against Gram-positive infections to inspiration for new scaffolds in drug discovery.

Research from Nature Portfolio

Studies of kistamicin biosynthesis have revealed how two cytochrome P450 Oxy enzymes, in conjunction with a unique NRPS X-domain, forge three aromatic crosslinks, including an unusual 15-membered A–O–B ring. Structural and functional analyses demonstrate that these Oxy enzymes engage the X-domain to achieve precise cyclisation and that one enzyme exhibits remarkable promiscuity, installing multiple crosslinks into synthetic peptide substrates containing phenolic residues. In vitro reconstitution of the complete P450 cascade has further clarified the order and interdependence of enzyme action during aglycone formation.

Investigations into teicoplanin biosynthesis have provided the first in vitro characterisation of the OxyE enzyme, responsible for the F–O–G ring formation. OxyE activity requires prior installation of an initial C–O–D crosslink by OxyB and direct interaction with the X-domain for catalytic turnover. Detailed kinetic and stereochemical studies reveal limited substrate flexibility that mirrors OxyB selectivity, and demonstrate that the sequence of P450 addition critically influences the efficiency of tricyclic peptide formation.

Glycopeptide Antibiotic Biosynthesis and Natural Product Chemistry publication trend

The graph below shows the total number of articles in glycopeptide antibiotic biosynthesis and natural product chemistry across all publications each year (not limited to Nature Index journals).

Technical terms

Glycopeptide antibiotic: A nonribosomal peptide antibiotic with multiple aromatic crosslinks, glycosylation and halogenation, exemplified by vancomycin and teicoplanin.

Nonribosomal peptide synthetase (NRPS): A modular enzyme complex that assembles peptide chains independently of the ribosome, using adenylation, thiolation and condensation domains.

Cytochrome P450 (Oxy) enzyme: A class of haem-containing monooxygenases that catalyse oxidative phenol coupling to create crosslinks in glycopeptide cores.

X-domain: A specialised docking domain within the NRPS that mediates recruitment of P450 enzymes for peptide cyclisation.

Peptidyl carrier protein (PCP) domain: A domain of NRPS that tethers activated amino acids or peptide intermediates via a phosphopantetheine arm.

Halogenase enzyme: An enzyme that introduces halogen atoms (e.g., chlorine) into aromatic residues of carrier-tethered substrates, influencing antibiotic potency.

References

1. Biological, chemical, and biochemical strategies for modifying glycopeptide antibiotics. Journal of Biological Chemistry (2019).
2. Kistamicin biosynthesis reveals the biosynthetic requirements for production of highly crosslinked glycopeptide antibiotics. Nature Communications (2019).
3. F-O-G Ring Formation in Glycopeptide Antibiotic Biosynthesis is Catalysed by OxyE. Scientific Reports (2016).
4. Bis-chlorination of a hexapeptide–PCP conjugate by the halogenase involved in vancomycin biosynthesis. Organic & Biomolecular Chemistry (2014).