Biotechnology

Genomics

Biology

Gene

Mode of action

Genome editing

Functional genomics

Genome

Metabolic pathway

Natural product

Dehydratase

Computational biology

Drug discovery

Biochemistry

Nature

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. Fungal genome mining targeted to self-resistance genes close to biosynthetic gene clusters identifies a pathway that produces aspterric acid, which proves to be a potent inhibitor of plant growth.

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