The long-term goal of this research is to understand the molecular action and resistance mechanisms of two important classes of insecticides, pyrethroids and sodium channel blocker insecticides (SCBIs). Strategies for the control of arthropod pests of major public health concerns continue to rely heavily on the use of relatively safe insecticides. Currently, pyrethroids are the only class of insecticides used in insecticide treated nets (ITNs) for malaria control, due to their fast acting, high efficacy, and relative low toxicity to humans. However, a major threat to the sustained use of pyrethroids is the development of resistance. Indoxacarb and its active metabolite (DCJW), the first member of a new class of SCBIs, also meets vector control criteria, and could be an alternative insecticide to pyrethroids. Both pyrethroids and indoxacarb target voltage-gated sodium channels;however, the modes of their action are not well understood at the molecular level, which presents a major obstacle to the characterization of mechanisms of resistance.
The specific aims of this renewal proposal are: 1) Characterization of the molecular basis of pyrethroid action and resistance, and 2) Identification of the receptor site and molecular action of indoxacarb/DCJW on sodium channels. A combination of molecular, electrophysiological, and computer modeling methods will be used to test novel hypotheses, with the final goal of defining the molecular identities of the elusive pyrethroid and indoxacarb receptor sites on the insect sodium channel. New knowledge gained from this fundamental research will have significant impact on future development of effective monitoring and management strategies for controlling major human health-threatening arthropod pests.

Public Health Relevance

This application describes basic research to understand how pyrethroid and indoxacarb insecticides interact with the voltage-gated sodium channel at the molecular level and how insect pests develop resistance to these insecticides. The knowledge gained from this research will have important implications for the development of strategies to control arthropod vectors that transmit important human diseases including malaria.

National Institute of Health (NIH)
National Institute of General Medical Sciences (NIGMS)
Research Project (R01)
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Vector Biology Study Section (VB)
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Nie, Zhongzhen
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Michigan State University
Schools of Arts and Sciences
East Lansing
United States
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Wu, Shaoying; Nomura, Yoshiko; Du, Yuzhe et al. (2017) Molecular basis of selective resistance of the bumblebee BiNav1 sodium channel to tau-fluvalinate. Proc Natl Acad Sci U S A 114:12922-12927
Chen, Mengli; Du, Yuzhe; Nomura, Yoshiko et al. (2017) Mutations of two acidic residues at the cytoplasmic end of segment IIIS6 of an insect sodium channel have distinct effects on pyrethroid resistance. Insect Biochem Mol Biol 82:1-10
Silver, Kristopher; Dong, Ke; Zhorov, Boris S (2017) Molecular Mechanism of Action and Selectivity of Sodium Ch annel Blocker Insecticides. Curr Med Chem 24:2912-2924
Chen, Mengli; Du, Yuzhe; Nomura, Yoshiko et al. (2017) Alanine to valine substitutions in the pore helix IIIP1 and linker-helix IIIL45 confer cockroach sodium channel resistance to DDT and pyrethroids. Neurotoxicology 60:197-206
Haddi, Khalid; Tomé, Hudson V V; Du, Yuzhe et al. (2017) Detection of a new pyrethroid resistance mutation (V410L) in the sodium channel of Aedes aegypti: a potential challenge for mosquito control. Sci Rep 7:46549
Zhorov, Boris S; Dong, Ke (2017) Elucidation of pyrethroid and DDT receptor sites in the voltage-gated sodium channel. Neurotoxicology 60:171-177
Wang, Xing-Liang; Su, Wen; Zhang, Jian-Heng et al. (2016) Two novel sodium channel mutations associated with resistance to indoxacarb and metaflumizone in the diamondback moth, Plutella xylostella. Insect Sci 23:50-8
Du, Yuzhe; Nomura, Yoshiko; Zhorov, Boris S et al. (2016) Evidence for Dual Binding Sites for 1,1,1-Trichloro-2,2-bis(p-chlorophenyl)ethane (DDT) in Insect Sodium Channels. J Biol Chem 291:4638-48
Hu, Zhaonong; Du, Yuzhe; Xiao, Xinmin et al. (2016) Insight into the Mode of Action of Haedoxan A from Phryma leptostachya. Toxins (Basel) 8:53
Zhang, Yongqiang; Du, Yuzhe; Jiang, Dingxin et al. (2016) The Receptor Site and Mechanism of Action of Sodium Channel Blocker Insecticides. J Biol Chem 291:20113-24

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