Analysis of modular bioengineered antimicrobial lanthipeptides at nanoliter scale.
- Schmitt S Department of Biosystems Science and Engineering, ETH Zürich, Basel, Switzerland.
- Montalbán-López M Department of Molecular Genetics, University of Groningen, Groningen, The Netherlands.
- Peterhoff D Institute of Medical Microbiology and Hygiene, University of Regensburg, Regensburg, Germany.
- Deng J Department of Molecular Genetics, University of Groningen, Groningen, The Netherlands.
- Wagner R Institute of Medical Microbiology and Hygiene, University of Regensburg, Regensburg, Germany.
- Held M Department of Biosystems Science and Engineering, ETH Zürich, Basel, Switzerland.
- Kuipers OP Department of Molecular Genetics, University of Groningen, Groningen, The Netherlands. o.p.kuipers@rug.nl.
- Panke S Department of Biosystems Science and Engineering, ETH Zürich, Basel, Switzerland. sven.panke@bsse.ethz.ch.
- 2019-04-03
Published in:
- Nature chemical biology. - 2019
Alanine
Anti-Bacterial Agents
Bacteria
Drug Design
Microbial Sensitivity Tests
Peptides
Protein Engineering
Sulfides
English
The rise of antibiotic resistance demands the acceleration of molecular diversification strategies to inspire new chemical entities for antibiotic medicines. We report here on the large-scale engineering of ribosomally synthesized and post-translationally modified antimicrobial peptides carrying the ring-forming amino acid lanthionine. New-to-nature variants featuring distinct properties were obtained by combinatorial shuffling of peptide modules derived from 12 natural antimicrobial lanthipeptides and processing by a promiscuous post-translational modification machinery. For experimental characterization, we developed the nanoFleming, a miniaturized and parallelized high-throughput inhibition assay. On the basis of a hit set of >100 molecules, we identified variants with improved activity against pathogenic bacteria and shifted activity profiles, and extrapolated design guidelines that will simplify the identification of peptide-based anti-infectives in the future.
- Language
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- English
- Open access status
- green
- Identifiers
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- DOI 10.1038/s41589-019-0250-5
- PMID 30936500
- Persistent URL
- https://sonar.ch/global/documents/238072
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