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Resistance mutation conserved between insects and mites unravels the benzoylurea insecticide mode of action on chitin biosynthesis

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Abstract
Despite the major role of chitin biosynthesis inhibitors such as benzoylureas (BPUs) in the control of pests in agricultural and public health for almost four decades, their molecular mode of action (MoA) has in most cases remained elusive. BPUs interfere with chitin biosynthesis and were thought to interact with sulfonylurea receptors that mediate chitin vesicle transport. Here, we uncover a mutation (I1042M) in the chitin synthase 1 (CHS1) gene of BPU-resistant Plutella xylostella at the same position as the I1017F mutation reported in spider mites that confers etoxazole resistance. Using a genome-editing CRISPR/Cas9 approach coupled with homology-directed repair (HDR) in Drosophila melanogaster, we introduced both substitutions (I1056M/F) in the corresponding fly CHS1 gene (kkv). Homozygous lines bearing either of these mutations were highly resistant to etoxazole and all tested BPUs, as well as buprofezin-an important hemipteran chitin biosynthesis inhibitor. This provides compelling evidence that BPUs, etoxazole, and buprofezin share in fact the same molecular MoA and directly interact with CHS. This finding has immediate effects on resistance management strategies of major agricultural pests but also on mosquito vectors of serious human diseases such as Dengue and Zika, as diflubenzuron, the standard BPU, is one of the few effective larvicides in use. The study elaborates on how genome editing can directly, rapidly, and convincingly elucidate the MoA of bioactive molecules, especially when target sites are complex and hard to reconstitute in vitro.
Keywords
insecticide resistance, benzoylureas, CRISPR/Cas9, resistance management, mosquito control, DIAMIDE INSECTICIDES, DIAMONDBACK MOTH, DROSOPHILA-MELANOGASTER, RYANODINE RECEPTOR, FUNCTIONAL-CHARACTERIZATION, SYNTHESIS INHIBITORS, TETRANYCHUS-URTICAE, PLUTELLA-XYLOSTELLA, MALARIA CONTROL, TARGET-SITE

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Citation

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Chicago
Douris, Vassilis, Denise Steinbach, Rafaela Panteleri, Ioannis Livadaras, John Anthony Pickett, Thomas Van Leeuwen, Ralf Nauen, and John Vontas. 2016. “Resistance Mutation Conserved Between Insects and Mites Unravels the Benzoylurea Insecticide Mode of Action on Chitin Biosynthesis.” Proceedings of the National Academy of Sciences of the United States of America 113 (51): 14692–14697.
APA
Douris, V., Steinbach, D., Panteleri, R., Livadaras, I., Pickett, J. A., Van Leeuwen, T., Nauen, R., et al. (2016). Resistance mutation conserved between insects and mites unravels the benzoylurea insecticide mode of action on chitin biosynthesis. PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA, 113(51), 14692–14697.
Vancouver
1.
Douris V, Steinbach D, Panteleri R, Livadaras I, Pickett JA, Van Leeuwen T, et al. Resistance mutation conserved between insects and mites unravels the benzoylurea insecticide mode of action on chitin biosynthesis. PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA. 2016;113(51):14692–7.
MLA
Douris, Vassilis, Denise Steinbach, Rafaela Panteleri, et al. “Resistance Mutation Conserved Between Insects and Mites Unravels the Benzoylurea Insecticide Mode of Action on Chitin Biosynthesis.” PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA 113.51 (2016): 14692–14697. Print.
@article{8502591,
  abstract     = {Despite the major role of chitin biosynthesis inhibitors such as benzoylureas (BPUs) in the control of pests in agricultural and public health for almost four decades, their molecular mode of action (MoA) has in most cases remained elusive. BPUs interfere with chitin biosynthesis and were thought to interact with sulfonylurea receptors that mediate chitin vesicle transport. Here, we uncover a mutation (I1042M) in the chitin synthase 1 (CHS1) gene of BPU-resistant Plutella xylostella at the same position as the I1017F mutation reported in spider mites that confers etoxazole resistance. Using a genome-editing CRISPR/Cas9 approach coupled with homology-directed repair (HDR) in Drosophila melanogaster, we introduced both substitutions (I1056M/F) in the corresponding fly CHS1 gene (kkv). Homozygous lines bearing either of these mutations were highly resistant to etoxazole and all tested BPUs, as well as buprofezin-an important hemipteran chitin biosynthesis inhibitor. This provides compelling evidence that BPUs, etoxazole, and buprofezin share in fact the same molecular MoA and directly interact with CHS. This finding has immediate effects on resistance management strategies of major agricultural pests but also on mosquito vectors of serious human diseases such as Dengue and Zika, as diflubenzuron, the standard BPU, is one of the few effective larvicides in use. The study elaborates on how genome editing can directly, rapidly, and convincingly elucidate the MoA of bioactive molecules, especially when target sites are complex and hard to reconstitute in vitro.},
  author       = {Douris, Vassilis and Steinbach, Denise and Panteleri, Rafaela and Livadaras, Ioannis and Pickett, John Anthony and Van Leeuwen, Thomas and Nauen, Ralf and Vontas, John},
  issn         = {0027-8424},
  journal      = {PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA},
  language     = {eng},
  number       = {51},
  pages        = {14692--14697},
  title        = {Resistance mutation conserved between insects and mites unravels the benzoylurea insecticide mode of action on chitin biosynthesis},
  url          = {http://dx.doi.org/10.1073/pnas.1618258113},
  volume       = {113},
  year         = {2016},
}

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