The glycopeptide antibiotics of the vancomycin family are potent antibacterial agents that can cure life-threatening bacterial infections by complexation of the D-Ala-D-Ala termini of peptidoglycan intermediates. The dramatic rise in resistance to vancomycin by grain positive pathogens (e.g., Vancomycin Resistant Enterococci) impels investigation into routes to more effective vancomycin analogs. Given the low likelihood of practical total syntheses, understanding of the enzymatic assembly of these nonribosomal peptide antibiotics offers prospect for subsequent reprogramming for combinatorial biosynthesis. This proposal deals with three phases of the enzymatic biosynthesis of vancomycin: (1) the beginning stages of the Nonribosomal Peptide Synthetase (NRPS) assembly line that makes the initial acyclic heptapeptide aglycone of vancomycin family members; (2) the post NRPS enzymatic tailoring of the heptapeptide, including oxidative crosslinking at the aryl side chains of residues 2,4,6,5 and 7, chlorination at 2 and 6, and glycosylation at 4 and 6; (3) the biogenesis of the 4-OH-phenylglycine incorporated at residues 4 and 5 of the core and 3,5-dihydroxyphenylglycine incorporated at residue 7. These aromatic amino acids are key sites for the crosslinking that produces the rigid cup-shaped architecture of the crosslinked core that enables recognition of the peptidoglycan termini and antibiotic action.
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