Resistance-gene-directed discovery of a natural-product herbicide with a new mode of action

Nature. 2018 Jul;559(7714):415-418. doi: 10.1038/s41586-018-0319-4. Epub 2018 Jul 11.


Bioactive natural products have evolved to inhibit specific cellular targets and have served as lead molecules for health and agricultural applications for the past century1-3. The post-genomics era has brought a renaissance in the discovery of natural products using synthetic-biology tools4-6. However, compared to traditional bioactivity-guided approaches, genome mining of natural products with specific and potent biological activities remains challenging4. Here we present the discovery and validation of a potent herbicide that targets a critical metabolic enzyme that is required for plant survival. Our approach is based on the co-clustering of a self-resistance gene in the natural-product biosynthesis gene cluster7-9, which provides insight into the potential biological activity of the encoded compound. We targeted dihydroxy-acid dehydratase in the branched-chain amino acid biosynthetic pathway in plants; the last step in this pathway is often targeted for herbicide development10. We show that the fungal sesquiterpenoid aspterric acid, which was discovered using the method described above, is a sub-micromolar inhibitor of dihydroxy-acid dehydratase that is effective as a herbicide in spray applications. The self-resistance gene astD was validated to be insensitive to aspterric acid and was deployed as a transgene in the establishment of plants that are resistant to aspterric acid. This herbicide-resistance gene combination complements the urgent ongoing efforts to overcome weed resistance11. Our discovery demonstrates the potential of using a resistance-gene-directed approach in the discovery of bioactive natural products.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Arabidopsis / drug effects
  • Arabidopsis / enzymology
  • Arabidopsis / genetics
  • Arabidopsis / growth & development
  • Biological Products / analysis
  • Biological Products / metabolism*
  • Biological Products / pharmacology*
  • Enzyme Inhibitors / analysis
  • Enzyme Inhibitors / pharmacology
  • Herbicide Resistance / genetics
  • Herbicides / analysis
  • Herbicides / metabolism*
  • Herbicides / pharmacology*
  • Heterocyclic Compounds, 3-Ring / analysis
  • Heterocyclic Compounds, 3-Ring / metabolism*
  • Heterocyclic Compounds, 3-Ring / pharmacology*
  • Hydro-Lyases / antagonists & inhibitors
  • Hydro-Lyases / chemistry
  • Hydro-Lyases / metabolism
  • Models, Molecular
  • Multigene Family / genetics
  • Plant Growth Regulators / analysis
  • Plant Growth Regulators / pharmacology
  • Plants, Genetically Modified / genetics
  • Transgenes / genetics


  • Biological Products
  • Enzyme Inhibitors
  • Herbicides
  • Heterocyclic Compounds, 3-Ring
  • Plant Growth Regulators
  • aspterric acid
  • Hydro-Lyases
  • dihydroxyacid dehydratase