Analysis of modular bioengineered antimicrobial lanthipeptides at nanoliter scale

Steven Schmitt, Manuel Montalbán-López, David Peterhoff, Jingjing Deng, Ralf Wagner, Martin Held, Oscar P Kuipers*, Sven Panke

*Corresponding author for this work

Research output: Contribution to journalArticleAcademicpeer-review

42 Citations (Scopus)
286 Downloads (Pure)

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.

Original languageEnglish
Pages (from-to)437-443
Number of pages8
JournalNature Chemical Biology
Volume15
Issue number5
Early online date1-Apr-2019
DOIs
Publication statusPublished - May-2019

Keywords

  • NATURAL-PRODUCTS
  • PEPTIDE
  • NISIN
  • BIOSYNTHESIS
  • LANTIBIOTICS
  • PROTEIN
  • LEADER
  • PROMISCUITY
  • MACHINERY
  • PLATFORM

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