Analysis of modular bioengineered antimicrobial lanthipeptides at nanoliter scale

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


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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Alanine / analogs & derivatives*
  • Alanine / chemistry
  • Alanine / metabolism
  • Alanine / pharmacology
  • Anti-Bacterial Agents / chemistry
  • Anti-Bacterial Agents / metabolism
  • Anti-Bacterial Agents / pharmacology*
  • Bacteria / drug effects*
  • Drug Design
  • Microbial Sensitivity Tests
  • Peptides / chemistry
  • Peptides / metabolism
  • Peptides / pharmacology*
  • Protein Engineering*
  • Sulfides / chemistry
  • Sulfides / metabolism
  • Sulfides / pharmacology*


  • Anti-Bacterial Agents
  • Peptides
  • Sulfides
  • lanthionine
  • Alanine