Differential metabolism of sulfoximine and neonicotinoid insecticides by Drosophila melanogaster monooxygenase CYP6G1

Sulfoxaflor [N-[methyloxido[1-[6-(trifluoromethyl)-3-pyridinyl]ethyl]-λ4-sulfanylidene] cyanamide] is in development as the first product from the new sulfoximine class of insect control agents. Highly effective against a variety of sap-feeding pest insects, available data indicate no cross-resistance to sulfoxaflor in pest insect strains that exhibit high levels of resistance to neonicotinoids and other insecticides. In vitro studies of the cytochrome P450 monooxygenase CYP6G1 from Drosophila melanogaster, expressed in a Drosophila cell line, show very high levels of metabolism for a variety of neonicotinoids, but not for sulfoxaflor and its chloropyridine-analog. A sulfoxaflor analog with nitrogen in place of the carbon in the bridge between the pyridine and sulfoximine moiety shows a modest degree of metabolism. In silico homology modeling of the CYP6G1 with the sulfoximines and neonicotinoids suggests that steric effects may limit interactions of the sulfoximines with the reactive heme-oxo complex. A distinct relationship was identified for the summed Hückel charges and the degree of metabolism observed. These observations help explain the lack of sulfoxaflor metabolism by CYP6G1, and in turn provide a basis for the lack of cross-resistance to sulfoxaflor in insecticide resistant strains of pest insects.

Graphical abstractFigure optionsDownload full-size imageDownload as PowerPoint slideHighlights► The monooxygenase CYP6G1 was cloned and expressed in D.mel-2 cells. ► Sulfoxaflor (SFX) and its chloropyridine-analog were not metabolized by CYP6G1. ► All neonicotinoids tested were metabolized by CYP6G1. ► Homology models of CYP6G1 suggest differences in binding between SFX and neonicotinoids. ► Differences in metabolism may explain the lack of cross-resistance to SFX.