Format

Send to

Choose Destination
Nat Chem Biol. 2019 May;15(5):437-443. doi: 10.1038/s41589-019-0250-5. Epub 2019 Apr 1.

Analysis of modular bioengineered antimicrobial lanthipeptides at nanoliter scale.

Author information

1
Department of Biosystems Science and Engineering, ETH Zürich, Basel, Switzerland.
2
Department of Molecular Genetics, University of Groningen, Groningen, The Netherlands.
3
Institute of Medical Microbiology and Hygiene, University of Regensburg, Regensburg, Germany.
4
Institute of Clinical Microbiology and Hygiene, University Hospital Regensburg, Regensburg, Germany.
5
Department of Molecular Genetics, University of Groningen, Groningen, The Netherlands. o.p.kuipers@rug.nl.
6
Department of Biosystems Science and Engineering, ETH Zürich, Basel, Switzerland. sven.panke@bsse.ethz.ch.

Abstract

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.

PMID:
30936500
DOI:
10.1038/s41589-019-0250-5
[Indexed for MEDLINE]

Supplemental Content

Full text links

Icon for Nature Publishing Group
Loading ...
Support Center