Biosynthesis, Synthesis, and Activities of Barnesin A, a NRPS-PKS Hybrid Produced by an Anaerobic Epsilonproteobacterium

ACS Chem Biol. 2018 Aug 17;13(8):1990-1995. doi: 10.1021/acschembio.8b00445. Epub 2018 Jun 25.


Despite the wealth of physiological knowledge and plentiful genomes available, only few natural products of anaerobic bacteria have been identified until today and even less have been linked to their biosynthetic gene cluster. Here, we analyzed a unique NRPS-PKS hybrid gene cluster from an anaerobic Epsilonproteobacterium ( Sulfurospirillum barnesii). Phylogenetic analysis of key biosynthetic genes, gene expression studies, and comparative metabolomics resulted in the identification of the first anoxically biosynthesized NRPS-PKS hybrid metabolite: a lipo-dipeptide with a vinylogous side chain, called barnesin A. The absolute structure was verified by a modular total synthesis, and barnesin and derivatives were found to have antimicrobial activity, as well as selective and nanomolar inhibitory activity, against pharmacological important cysteine proteases, such as cathepsin B.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Anti-Bacterial Agents / biosynthesis
  • Anti-Bacterial Agents / chemical synthesis
  • Anti-Bacterial Agents / pharmacology
  • Campylobacteraceae / chemistry*
  • Campylobacteraceae / genetics*
  • Cysteine Proteinase Inhibitors / chemical synthesis
  • Cysteine Proteinase Inhibitors / pharmacology
  • Dipeptides / biosynthesis
  • Dipeptides / chemical synthesis
  • Dipeptides / pharmacology*
  • Lipopeptides / biosynthesis
  • Lipopeptides / chemical synthesis
  • Lipopeptides / pharmacology*
  • Multigene Family*
  • Mycobacterium / drug effects
  • Phylogeny
  • Pseudomonas aeruginosa / drug effects
  • Staphylococcus aureus / drug effects


  • Anti-Bacterial Agents
  • Cysteine Proteinase Inhibitors
  • Dipeptides
  • Lipopeptides