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

Yan Yan, Qikun Liu, Xin Zang, Shuguang Yuan, Undramaa Bat-Erdene, Calvin Nguyen, Jianhua Gan, Jiahai Zhou (), Steven E. Jacobsen () and Yi Tang ()
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Yan Yan: University of California Los Angeles
Qikun Liu: University of California Los Angeles
Xin Zang: State Key Laboratory of Bio-organic and Natural Products Chemistry, Center for Excellence in Molecular Synthesis, Shanghai Institute of Organic Chemistry, Chinese Academy of Sciences
Shuguang Yuan: Laboratory of Physical Chemistry of Polymers and Membranes, Ecole Polytechnique Fédérale de Lausanne
Undramaa Bat-Erdene: University of California Los Angeles
Calvin Nguyen: University of California Los Angeles
Jianhua Gan: State Key Laboratory of Genetic Engineering, Collaborative Innovation Center of Genetics and Development, Department of Physiology and Biophysics, School of Life Sciences, Fudan University
Jiahai Zhou: State Key Laboratory of Bio-organic and Natural Products Chemistry, Center for Excellence in Molecular Synthesis, Shanghai Institute of Organic Chemistry, Chinese Academy of Sciences
Steven E. Jacobsen: University of California Los Angeles
Yi Tang: University of California Los Angeles

Nature, 2018, vol. 559, issue 7714, 415-418

Abstract: Abstract 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.

Date: 2018
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DOI: 10.1038/s41586-018-0319-4

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