RT Journal Article SR Electronic T1 Phazolicin – a Novel Thiazole/Oxazole-Modified Peptide Inhibiting the Bacterial Ribosome in a Species-Specific Way JF bioRxiv FD Cold Spring Harbor Laboratory SP 705970 DO 10.1101/705970 A1 Dmitrii Y. Travin A1 Zoe L. Watson A1 Mikhail Metelev A1 Fred R. Ward A1 Ilya A. Osterman A1 Irina M. Khven A1 Nelli F. Khabibullina A1 Marina Serebryakova A1 Peter Mergaert A1 Yury S. Polikanov A1 Jamie H. D. Cate A1 Konstantin Severinov YR 2019 UL http://biorxiv.org/content/early/2019/07/18/705970.abstract AB Ribosomally synthesized and post-translationally modified peptides (RiPPs) are a rapidly expanding and largely untapped class of natural products with various biological activities. Linear azol(in)e-containing peptides (LAPs) comprise a subclass of RiPPs that display an outstanding diversity of mechanisms of action while sharing common structural features. Here, we report the discovery of a new LAP biosynthetic gene cluster in the genome of Rhizobium sp. Pop5, which encodes the precursor peptide and modification machinery of phazolicin (PHZ) – an extensively modified peptide exhibiting narrow-spectrum antibacterial activity against some symbiotic bacteria of leguminous plants belonging to the Rhizobiales. PHZ inhibits prokaryotic translation through the obstruction of the passage of the nascent peptide through the ribosome exit channel. The cryo-EM structure of the Escherichia coli ribosome with bound PHZ revealed that the drug interacts with the 23S rRNA and ribosomal proteins uL4 and uL22 and obstructs the exit tunnel in a way that is distinct from other compounds blocking the exit channel. We show that the sequence of uL4 ribosomal protein loop involved in PHZ binding determines the species-specificity of antibiotic interaction with its target. PHZ and its predicted homologs from other bacterial species expand the known diversity of LAPs and may be used in the future as biocontrol agents for the needs of agriculture.