A gatekeeper enzyme in the biosynthesis of indolmycin

Molecules discovered in the “golden age of antibiotics” are increasingly being revisited in an era where new antibiotics are desperately needed. One of these molecules, the bacterial tryptophanyl-tRNA synthetase inhibitor indolmycin, features a unique oxazolinone heterocycle whose biogenetic origins have remained obscure for over 50 years. We have identified and characterized the indolmycin biosynthetic pathway. Our work revealed the decades-long mystery of how the characteristic core oxazolinone ring is assembled from tryptophan- and arginine-derived metabolites. Our efforts have furthermore shown the key role of a gatekeeper enzyme, which acts to re-route metabolites away from a unique shunt product. Our work reveals the complete pathway for indolmycin formation and sets the stage for using genetic and chemo-enzymatic methods to generate new indolmycin derivatives as potential therapeutic agents.