Nootkatone is a sesquiterpene with known acaricidal and repellent properties, receiving registration by the EPA in 2020 for use as an insecticide or repellent. Previous research failed to determine the mechanism of toxicity for nootkatone and thus, we aimed to provide evidence suggesting the likely molecular target driving nootkatone toxicity. In silico molecular overlays of nootkatone and picrotoxinin, a known GABA antagonist, indicated the two molecules have strong structural commonality and share electrostatic arrangement. Considering these structural similarities, we employed toxicological and electrophysiological methods to determine if the putative mode of toxicity is through GABA-gated chloride channels. Topical application of nootkatone to a susceptible (CSOR) strain of Drosophila melanogaster yielded an LD50 of 45 (16-110) µg/mg, which was 10.7-fold more toxic when compared to the dieldrin-resistant (RDL1675) strain. Further, significant differences in nerve firing after application of nootkatone between the RDL1675 and CSOR strain were observed. Two minutes after application of 100 µM nootkatone, nerve firing was reduced to 78 ± 17% of baseline in the CSOR strain, which was significantly different from the 24 ± 11% of baseline firing observed in the RDL1675 strain (p = 0.035). For CSOR, 100 µM nootkatone significantly reversed GABA-mediated block, yet no statistically significant reversal was observed in the RDL1675 strain. Patch clamp recordings on D. melanogaster central neurons mirrored the extracellular results, where nootkatone inhibited chloride current by 62% ± 14% at 100 µM, whereas chloride current was inhibited approximately 3-fold less at 100 µM in RDL1675. Taken together, these data suggest nootkatone toxicity in D. melanogaster is mediated through GABA receptor antagonism.

Mechanism of Toxicity for the Sesquiterpene, Nootkatone

ACS Fall 2021

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