P450 Disruption Reveals Unforeseen Biaryl Cross-Link Chemistry in Glycopeptide Antibiotics.

Glycopeptide antibiotics (GPAs) are the drug of choice for treating multidrug-resistant Gram-positive infections. GPAs possess a unique aromatic amino-acid-rich scaffold interconnected by a diverse set of biaryl cross-links, contributing to their rigid 3D structures for specific target binding on the cell wall. Disruption of the P450 genes responsible for biaryl linkage formation from the biosynthetic gene cluster of varsomycin identified a never-before-seen macrocyclic ring system in GPA, which greatly expands the chemical space of GPAs.