Inactivation of P450 Reprograms the Ring Topology of Glycopeptide Antibiotics

Glycopeptide antibiotics (GPAs) are the drugs of choice for life-threatening Gram-positive infections and feature a biphenolic coupling cross-linked peptide scaffold constructed by certain P450s in a strict sequence- and position-specific manner. However, in situ point mutation of P450 within the fumamycin biosynthetic gene cluster uncovered new derivatives possessing previously inaccessible cross-link patterns, suggesting that P450 inactivation can reprogram the ring topology of GPAs and thereby could be used to expand their chemical space.