3 years ago

Identification of the Biosynthetic Pathway for the Antibiotic Bicyclomycin

Identification of the Biosynthetic Pathway for the Antibiotic Bicyclomycin
Kevin C. Santa Maria, Jon B. Patteson, Bo Li, Rachel A. Johnson, Wenlong Cai
Diketopiperazines (DKPs) make up a large group of natural products with diverse structures and biological activities. Bicyclomycin is a broad-spectrum DKP antibiotic with unique structure and function: it contains a highly oxidized bicyclic [4.2.2] ring and is the only known selective inhibitor of the bacterial transcription termination factor, Rho. Here, we identify the biosynthetic gene cluster for bicyclomycin containing six iron-dependent oxidases. We demonstrate that the DKP core is made by a tRNA-dependent cyclodipeptide synthase, and hydroxylations on two unactivated sp3 carbons are performed by two mononuclear iron, α-ketoglutarate-dependent hydroxylases. Using bioinformatics, we also identify a homologous gene cluster prevalent in a human pathogen Pseudomonas aeruginosa. We detect bicyclomycin by overexpressing this gene cluster and establish P. aeruginosa as a new producer of bicyclomycin. Our work uncovers the biosynthetic pathway for bicyclomycin and sheds light on the intriguing oxidation chemistry that converts a simple DKP into a powerful antibiotic.

Publisher URL: http://dx.doi.org/10.1021/acs.biochem.7b00943

DOI: 10.1021/acs.biochem.7b00943

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