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Resistance-gene-directed discovery of a natural-product herbicide with a new mode of action
Nature ( IF 50.5 ) Pub Date : 2018-07-01 , DOI: 10.1038/s41586-018-0319-4
Yan Yan , Qikun Liu , Xin Zang , Shuguang Yuan , Undramaa Bat-Erdene , Calvin Nguyen , Jianhua Gan , Jiahai Zhou , Steven E. Jacobsen , Yi Tang

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.

中文翻译:

抗性基因定向发现具有新作用模式的天然产物除草剂

生物活性天然产物已经进化到可以抑制特定的细胞目标,并在过去的一个世纪 1-3 中作为健康和农业应用的先导分子。后基因组时代带来了使用合成生物学工具发现天然产物的复兴4-6。然而,与传统的生物活性引导方法相比,具有特定和有效生物活性的天然产物的基因组挖掘仍然具有挑战性4。在这里,我们介绍了一种针对植物生存所需的关键代谢酶的强效除草剂的发现和验证。我们的方法基于天然产物生物合成基因簇 7-9 中自抗基因的共簇,这提供了对编码化合物潜在生物活性的洞察。我们针对植物支链氨基酸生物合成途径中的二羟酸脱水酶;该途径的最后一步通常针对除草剂开发10。我们表明,使用上述方法发现的真菌倍半萜类天冬氨酸是二羟基酸脱水酶的亚微摩尔抑制剂,在喷雾应用中作为除草剂是有效的。自抗基因 astD 被证实对紫草酸不敏感,并作为转基因用于建立对紫草酸有抗性的植物。这种除草剂抗性基因组合补充了克服杂草抗性的紧迫的持续努力11。我们的发现证明了使用抗性基因导向方法发现生物活性天然产物的潜力。
更新日期:2018-07-01
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