Gene Replacement for the Generation of Designed Novel Avermectin Derivatives with Enhanced Acaricidal and Nematicidal Activities
Gene Replacement for the Generation of Designed Novel Avermectin Derivatives with Enhanced Acaricidal and Nematicidal Activities
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DOI：
10.1128/aem.01025-15
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发表时间：
2015-08-01
影响因子：
4.4
通讯作者：
Zheng, Yu-Guo
中科院分区：
文献类型：
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作者：
Huang, Jun;Chen, An-Liang;Zheng, Yu-Guo
阿维菌素（AVM）和伊维菌素（IVM）是近30年来广泛使用的强效杀虫剂和杀螨剂。随着昆虫对 AVM 和 IVM 的抗性大大增强，迫切需要替代品。在这里，我们报道了两种新型AVM衍生物，tenvermectin A (TVM A)和TVM B，它们被认为是潜在的新一代农兽药。 TVM 的分子是根据 AVM、IVM 和米尔贝霉素 (MBM) 之间的结构和药理特性比较而设计的。为了生产 TVM，从 AVM 工业菌株阿维链霉菌 G8-17 构建了基因工程菌株 MHJ1011。在 MHJ1011 中，天然 aveA1 基因被吸水链霉菌的 milA1 无缝替换。 MHJ1011产生的两种TVM的总滴度达到3,400毫克/升。杀虫试验证明，TVM 增强了对朱砂叶螨和松材线虫的活性，符合预期。该研究为通过聚酮合酶（PKS）重组基因替换的新方法探索新型活性化合物提供了典型的例子。杀虫试验的结果可能有助于阐明 AVM 和 MBM 的构效关系。
Avermectin (AVM) and ivermectin (IVM) are potent pesticides and acaricides which have been widely used during the past 30 years. As insect resistance to AVM and IVM is greatly increasing, alternatives are urgently needed. Here, we report two novel AVM derivatives, tenvermectin A (TVM A) and TVM B, which are considered a potential new generation of agricultural and veterinary drugs. The molecules of the TVMs were designed based on structure and pharmacological property comparisons among AVM, IVM, and milbemycin (MBM). To produce TVMs, a genetically engineered strain, MHJ1011, was constructed from Streptomyces avermitilis G8-17, an AVM industrial strain. In MHJ1011, the native aveA1 gene was seamlessly replaced with milA1 from Streptomyces hygroscopicus. The total titer of the two TVMs produced by MHJ1011 reached 3,400 mg/liter. Insecticidal tests proved that TVM had enhanced activities against Tetranychus cinnabarinus and Bursaphelenchus xylophilus, as desired. This study provides a typical example of exploration for novel active compounds through a new method of polyketide synthase (PKS) reassembly for gene replacement. The results of the insecticidal tests may be of use in elucidating the structure-activity relationship of AVMs and MBMs.