Unravelling nicotinic receptor and ligand features underlying neonicotinoid knockdown actions on the malaria vector mosquito .

With the spread of resistance to long-established insecticides targeting malaria vectors, understanding the actions of compounds newly identified for vector control is essential. With new commercial vector-control products containing neonicotinoids under development, we investigate the actions of 6 neonicotinoids (imidacloprid, thiacloprid, clothianidin, dinotefuran, nitenpyram and acetamiprid) on 13 nicotinic acetylcholine receptor (nAChR) subtypes produced by expression of combinations of the Ag1, Ag2, Ag3, Ag8 and Ag1 subunits in oocytes, the orthologues of which we have previously shown to be important in neonicotinoid actions. The presence of the Ag2 subunit reduces neonicotinoid affinity for the mosquito nAChRs, whereas the Ag3 subunit increases it. Crystal structures of the acetylcholine binding protein (AChBP), an established surrogate for the ligand-binding domain, with dinotefuran bound, shows a unique target site interaction through hydrogen bond formation and CH-N interaction at the tetrahydrofuran ring. This is of interest as dinotefuran is also under trial as the toxic element in baited traps. Multiple regression analyses show a correlation between the efficacy of neonicotinoids for the Ag1/Ag2/Ag8/Ag1 nAChR, their hydrophobicity and their rate of knockdown of adult female , providing new insights into neonicotinoid features important for malaria vector control.