title: Gene Replacement for the Generation of Designed Novel Avermectin Derivatives with Enhanced Acaricidal and Nematicidal Activities.
abstract: 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.
authors.affiliation: Institute of Bioengineering, Zhejiang University of Technology, Hangzhou, China Central Research Institute, Zhejiang Hisun Pharmaceutical Co. Ltd., Taizhou, China.
authors.forename: Jun
authors.initials: J
authors.lastname: Huang
authors.affiliation: Provincial Joint Engineering Laboratory of Biopesticide Preparation, Zhejiang Agricultural and Forestry University, Lin'An, China.
authors.forename: An-Liang
authors.initials: AL
authors.lastname: Chen
authors.affiliation: Central Research Institute, Zhejiang Hisun Pharmaceutical Co. Ltd., Taizhou, China.
authors.forename: Hui
authors.initials: H
authors.lastname: Zhang
authors.affiliation: Central Research Institute, Zhejiang Hisun Pharmaceutical Co. Ltd., Taizhou, China.
authors.forename: Zhen
authors.initials: Z
authors.lastname: Yu
authors.affiliation: Central Research Institute, Zhejiang Hisun Pharmaceutical Co. Ltd., Taizhou, China.
authors.forename: Mei-Hong
authors.initials: MH
authors.lastname: Li
authors.affiliation: Central Research Institute, Zhejiang Hisun Pharmaceutical Co. Ltd., Taizhou, China.
authors.forename: Na
authors.initials: N
authors.lastname: Li
authors.affiliation: Central Research Institute, Zhejiang Hisun Pharmaceutical Co. Ltd., Taizhou, China.
authors.forename: Jia-Tan
authors.initials: JT
authors.lastname: Lin
authors.affiliation: Central Research Institute, Zhejiang Hisun Pharmaceutical Co. Ltd., Taizhou, China.
authors.forename: Hua
authors.initials: H
authors.lastname: Bai
authors.affiliation: Provincial Joint Engineering Laboratory of Biopesticide Preparation, Zhejiang Agricultural and Forestry University, Lin'An, China Central Research Institute, Zhejiang Hisun Pharmaceutical Co. Ltd., Taizhou, China jdwang@hisunpharm.com zhengyg@zjut.edu.cn.
authors.forename: Ji-Dong
authors.initials: JD
authors.lastname: Wang
authors.affiliation: Institute of Bioengineering, Zhejiang University of Technology, Hangzhou, China jdwang@hisunpharm.com zhengyg@zjut.edu.cn.
authors.forename: Yu-Guo
authors.initials: YG
authors.lastname: Zheng
mesh_terms: D056810:Acaricides / Q000737:chemistry / Q000378:metabolism*; D000818:Animals; D000871:Anthelmintics / Q000737:chemistry / Q000378:metabolism*; D007559:Ivermectin / Q000031:analogs & derivatives* / Q000737:chemistry / Q000378:metabolism; D060847:Metabolic Engineering; D015394:Molecular Structure; D021261:Parasitic Sensitivity Tests; D013302:Streptomyces / Q000235:genetics* / Q000378:metabolism*; D016019:Survival Analysis; D040102:Tetranychidae / Q000187:drug effects; D017187:Tylenchida / Q000187:drug effects
chemical_list: D056810:Acaricides; D000871:Anthelmintics; D007559:Ivermectin; C019264:avermectin