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. Donk (), Douglas A. Mitchell () and Huimin Zhao ()
Additional contact information
Richard S. Ayikpoe: University of Illinois at Urbana-Champaign
Chengyou Shi: University of Illinois at Urbana-Champaign
Alexander J. Battiste: University of Illinois at Urbana-Champaign
Sara M. Eslami: University of Illinois at Urbana-Champaign
Sangeetha Ramesh: University of Illinois at Urbana-Champaign
Max A. Simon: University of Illinois at Urbana-Champaign
Ian R. Bothwell: University of Illinois at Urbana-Champaign
Hyunji Lee: University of Illinois at Urbana-Champaign
Andrew J. Rice: University of Illinois at Urbana-Champaign
Hengqian Ren: University of Illinois at Urbana-Champaign
Qiqi Tian: University of Illinois at Urbana-Champaign
Lonnie A. Harris: University of Illinois at Urbana-Champaign
Raymond Sarksian: University of Illinois at Urbana-Champaign
Lingyang Zhu: University of Illinois at Urbana-Champaign
Autumn M. Frerk: University of Illinois at Urbana-Champaign
Timothy W. Precord: University of Illinois at Urbana-Champaign
Wilfred A. Donk: University of Illinois at Urbana-Champaign
Douglas A. Mitchell: University of Illinois at Urbana-Champaign
Huimin Zhao: University of Illinois at Urbana-Champaign

Nature Communications, 2022, vol. 13, issue 1, 1-15

Abstract: Abstract 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.

Date: 2022
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DOI: 10.1038/s41467-022-33890-w

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