A scalable platform to discover antimicrobials of ribosomal origin

Richard S. Ayikpoe, Chengyou Shi, Alexander J. Battiste, Sara M. Eslami, Sangeetha Ramesh, Max A. Simon, Ian R. Bothwell, Hyunji Lee, Andrew J. Rice, Hengqian Ren, Qiqi Tian, Lonnie A. Harris, Raymond Sarksian, Lingyang Zhu, Autumn M. Frerk, Timothy W. Precord, Wilfred A. van der Donk, Douglas A. Mitchell, Huimin Zhao

Research output: Contribution to journalArticlepeer-review


Ribosomally synthesized and post-translationally modified peptides (RiPPs) are a promising source of new antimicrobials in the face of rising antibiotic resistance. Here, we report a scalable platform that combines high-throughput bioinformatics with automated biosynthetic gene cluster refactoring for rapid evaluation of uncharacterized gene clusters. As a proof of concept, 96 RiPP gene clusters that originate from diverse bacterial phyla involving 383 biosynthetic genes are refactored in a high-throughput manner using a biological foundry with a success rate of 86%. Heterologous expression of all successfully refactored gene clusters in Escherichia coli enables the discovery of 30 compounds covering six RiPP classes: lanthipeptides, lasso peptides, graspetides, glycocins, linear azol(in)e-containing peptides, and thioamitides. A subset of the discovered lanthipeptides exhibit antibiotic activity, with one class II lanthipeptide showing low µM activity against Klebsiella pneumoniae, an ESKAPE pathogen. Overall, this work provides a robust platform for rapidly discovering RiPPs.

Original languageEnglish (US)
Article number6135
JournalNature communications
Issue number1
StatePublished - Dec 2022

ASJC Scopus subject areas

  • General Chemistry
  • General Biochemistry, Genetics and Molecular Biology
  • General Physics and Astronomy


Dive into the research topics of 'A scalable platform to discover antimicrobials of ribosomal origin'. Together they form a unique fingerprint.

Cite this