DEET repels ORNery mosquitoes.

D EET ([N-N]-diethyl-mtoluamide) is widely used around the world as a repellent for mosquitoes and other biting insects. It was originally identified by a structure–activity study using synthetic compounds (1). Recently, a number of new compounds with similar activity [e.g., picaridine (2)] have been identified, but DEET remains the gold standard. Despite a tremendous number of studies (3), however, a plausible and evidence-based mechanism for DEET’s action has remained elusive. In a recent study, Ditzen et al. (4) wrote, ‘‘Here we show that DEET blocks electrophysiological responses to olfactory sensory neurons to attractive odors in Anopheles gambiae and Drosophila melanogaster’’ (Fig. 1A). However, in this issue of PNAS, Syed and Leal (5) present a new mechanism that demonstrates that mosquitoes detect DEET by means of olfaction and that this is the direct cause of their avoidance behavior (Fig. 1B). Various classes of compounds are termed ‘‘insect repellents.’’ Some, such as pyrethroids (e.g., the recently developed metofluthrin) and DDT, work by insecticidal effect, whereby sublethal toxicity causes the insect either to be ineffective in its attack or to escape from the region of insecticide application. Repellency, however, should relate to a behavioral effect caused by perception at the peripheral sensory nervous system, causing the insect to not bite and to leave the prospective host, with true behavioral repellency involving avoidance of the source of the repellent material, whether placed on the prospective host or near it. Until recently, two main classes of behavioral insect repellents were known: (i) those, like DEET and picaridine, that have been obtained through testing synthetic compounds for repellency in one of the forms discussed above; and (ii) those that include a wide range of plant essential oil components, often with strong aromas as perceived by humans, that act against blood-seeking insects presumably by suggesting a strong plant ecosystem. For best effect, DEET requires good skin coverage, but even with that, the insects can remain in an irritating cloud around the protected individual. (This is particularly evident with the Scottish biting midge, Culicoides impunctatus.) The alternative, plant-derived compounds are highly volatile and can repel the insects from the region of the host but usually require frequent application. In addition, some insects apparently can still detect the host by means of a highly sensitive and selective olfactory-based host-location capability. More recently, successful attempts have been made to identify experimental repellents derived from species closely related to the host range but not naturally acting as hosts (6, 7). There is also considerable promise in repellents active against the malaria mosquito (An. gambiae), the yellow fever mosquito (Aedes aegypti), and C. impunctatus that have been identified from odors collected by air entrainment of humans who show little or no attractiveness to these insects and from cases where attractiveness is naturally masked by the specific compounds giving rise to this repellency (ref. 8 and J.G.L., N. J. Seal, J. I. Cook, N. M. Stanczyk, M.A.B., S. J. Clark, S. A. Gezan, L. J. Wadhams, and J.A.P., unpublished data). Nonetheless, the repellent value of DEET and other compounds derived from structure–activity studies far outweighs other currently available repellents, so understanding the mechanism by which DEET acts remains of paramount importance. Syed and Leal (5) demonstrate the existence in some insects of specific ol-