A scalable platform to discover antimicrobials of ribosomal origin.

Autor: Ayikpoe RS; Department of Chemistry, University of Illinois at Urbana-Champaign, Urbana, 61801, IL, USA.; Carl R. Woese Institute for Genomic Biology, University of Illinois at Urbana-Champaign, Urbana, 61801, IL, USA., Shi C; Carl R. Woese Institute for Genomic Biology, University of Illinois at Urbana-Champaign, Urbana, 61801, IL, USA.; Department of Chemical and Biomolecular Engineering, University of Illinois at Urbana-Champaign, Urbana, 61801, IL, USA., Battiste AJ; Department of Chemistry, University of Illinois at Urbana-Champaign, Urbana, 61801, IL, USA.; Carl R. Woese Institute for Genomic Biology, University of Illinois at Urbana-Champaign, Urbana, 61801, IL, USA., Eslami SM; Department of Chemistry, University of Illinois at Urbana-Champaign, Urbana, 61801, IL, USA.; Carl R. Woese Institute for Genomic Biology, University of Illinois at Urbana-Champaign, Urbana, 61801, IL, USA., Ramesh S; Carl R. Woese Institute for Genomic Biology, University of Illinois at Urbana-Champaign, Urbana, 61801, IL, USA.; Department of Microbiology, University of Illinois at Urbana-Champaign, Urbana, 61801, IL, USA., Simon MA; Carl R. Woese Institute for Genomic Biology, University of Illinois at Urbana-Champaign, Urbana, 61801, IL, USA.; Department of Bioengineering, University of Illinois at Urbana-Champaign, Urbana, 61801, IL, USA., Bothwell IR; Department of Chemistry, University of Illinois at Urbana-Champaign, Urbana, 61801, IL, USA.; Carl R. Woese Institute for Genomic Biology, University of Illinois at Urbana-Champaign, Urbana, 61801, IL, USA., Lee H; Department of Chemistry, University of Illinois at Urbana-Champaign, Urbana, 61801, IL, USA.; Carl R. Woese Institute for Genomic Biology, University of Illinois at Urbana-Champaign, Urbana, 61801, IL, USA., Rice AJ; Department of Chemistry, University of Illinois at Urbana-Champaign, Urbana, 61801, IL, USA.; Carl R. Woese Institute for Genomic Biology, University of Illinois at Urbana-Champaign, Urbana, 61801, IL, USA., Ren H; Carl R. Woese Institute for Genomic Biology, University of Illinois at Urbana-Champaign, Urbana, 61801, IL, USA.; Department of Chemical and Biomolecular Engineering, University of Illinois at Urbana-Champaign, Urbana, 61801, IL, USA., Tian Q; Carl R. Woese Institute for Genomic Biology, University of Illinois at Urbana-Champaign, Urbana, 61801, IL, USA.; Department of Biochemistry, University of Illinois at Urbana-Champaign, Urbana, 61801, IL, USA., Harris LA; Department of Chemistry, University of Illinois at Urbana-Champaign, Urbana, 61801, IL, USA.; Carl R. Woese Institute for Genomic Biology, University of Illinois at Urbana-Champaign, Urbana, 61801, IL, USA., Sarksian R; Department of Chemistry, University of Illinois at Urbana-Champaign, Urbana, 61801, IL, USA.; Carl R. Woese Institute for Genomic Biology, University of Illinois at Urbana-Champaign, Urbana, 61801, IL, USA., Zhu L; School of Chemical Sciences NMR Laboratory, University of Illinois at Urbana-Champaign, Urbana, 61801, IL, USA., Frerk AM; Department of Chemistry, University of Illinois at Urbana-Champaign, Urbana, 61801, IL, USA.; Carl R. Woese Institute for Genomic Biology, University of Illinois at Urbana-Champaign, Urbana, 61801, IL, USA., Precord TW; Department of Chemistry, University of Illinois at Urbana-Champaign, Urbana, 61801, IL, USA.; Carl R. Woese Institute for Genomic Biology, University of Illinois at Urbana-Champaign, Urbana, 61801, IL, USA., van der Donk WA; Department of Chemistry, University of Illinois at Urbana-Champaign, Urbana, 61801, IL, USA. vddonk@illinois.edu.; Carl R. Woese Institute for Genomic Biology, University of Illinois at Urbana-Champaign, Urbana, 61801, IL, USA. vddonk@illinois.edu.; Department of Bioengineering, University of Illinois at Urbana-Champaign, Urbana, 61801, IL, USA. vddonk@illinois.edu.; Department of Biochemistry, University of Illinois at Urbana-Champaign, Urbana, 61801, IL, USA. vddonk@illinois.edu.; Howard Hughes Medical Institute, 4000 Jones Bridge Road, Chevy Chase, 20815, MD, USA. vddonk@illinois.edu., Mitchell DA; Department of Chemistry, University of Illinois at Urbana-Champaign, Urbana, 61801, IL, USA. douglasm@illinois.edu.; Carl R. Woese Institute for Genomic Biology, University of Illinois at Urbana-Champaign, Urbana, 61801, IL, USA. douglasm@illinois.edu.; Department of Microbiology, University of Illinois at Urbana-Champaign, Urbana, 61801, IL, USA. douglasm@illinois.edu., Zhao H; Department of Chemistry, University of Illinois at Urbana-Champaign, Urbana, 61801, IL, USA. zhao5@illinois.edu.; Carl R. Woese Institute for Genomic Biology, University of Illinois at Urbana-Champaign, Urbana, 61801, IL, USA. zhao5@illinois.edu.; Department of Chemical and Biomolecular Engineering, University of Illinois at Urbana-Champaign, Urbana, 61801, IL, USA. zhao5@illinois.edu.; Department of Bioengineering, University of Illinois at Urbana-Champaign, Urbana, 61801, IL, USA. zhao5@illinois.edu.
Jazyk: angličtina
Zdroj: Nature communications [Nat Commun] 2022 Oct 17; Vol. 13 (1), pp. 6135. Date of Electronic Publication: 2022 Oct 17.
DOI: 10.1038/s41467-022-33890-w
Abstrakt: 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.
(© 2022. The Author(s).)
Databáze: MEDLINE
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