Every year, approximately 700,000 people die from complications associated with etiologic disease agents transmitted by mosquitoes. While insecticide-based vector control strategies are important for the management of mosquito-borne diseases, insecticide-resistance and other logistical hurdles may lower the efficacy of this approach, especially in developing countries. Repellent technologies represent another fundamental aspect of preventing mosquito-borne disease transmission. Among these technologies, spatial repellents are promising alternatives to the currently utilized contact repellents and may significantly aid in the prevention of mosquito-borne disease if properly incorporated into integrated pest management approaches. As their deployment would not rely on prohibitively expensive or impractical novel accessory technologies and resources, they have potential utility in developing countries where the burden of mosquito-borne disease is most prevalent. This review aims to describe the history of various repellent technologies, highlight the potential of repellent technologies in preventing the spread of mosquito-borne disease, and discuss currently known mechanisms that confer resistance to current contact and spatial repellents, which may lead to the failures of these repellents. In the subsequent section, current and future research projects aimed at exploring long-lasting non-pyrethroid spatial repellent molecules along with new paradigms and rationale for their development will be discussed.

Mosquito-borne diseases account for the deaths of approximately 700,000 people annually throughout the world, with many more succumbing to the debilitating side effects associated with these etiologic disease agents. This is exacerbated in many countries where the lack of mosquito control and resources to prevent and treat mosquito-borne disease coincide. As populations of mosquito species grow more resistant to currently utilized control chemistries, the need for new and effective chemical means for vector control is more important than ever. Previous work revealed that plant essential oils enhance the toxicity of permethrin against multiple mosquito species that are of particular importance to public health. In this study, we screened permethrin and deltamethrin in combination with plant essential oils against a pyrethroid-susceptible and a pyrethroid-resistant strain of both Aedes aegypti and Anopheles gambiae. A number of plant essential oils significantly enhanced the toxicity of pyrethroids equal to or better than piperonyl butoxide, a commonly used synthetic synergist, in all strains tested. Significant synergism of pyrethroids was also observed for specific combinations of plant essential oils and pyrethroids. Moreover, plant essential oils significantly inhibited both cytochrome P450 and glutathione S-transferase activities, suggesting that the inhibition of detoxification contributes to the enhancement or synergism of plant essential oils for pyrethroids. This study highlights the potential of using diverse plant oils as insecticide additives to augment the efficacy of insecticidal formulations.

: Pyrethroid resistance is a significant threat to agricultural, urban and public health pest control activities. Because economic incentives for the production of novel active ingredients for the control of public health pests are lacking, this field is particularly affected by the potential failure of pyrethroid‐based insecticides brought about by increasing pyrethroid resistance. As a result, innovative approaches are desperately needed to overcome insecticide resistance, particularly in mosquitoes that transmit deadly and debilitating pathogens. Numerous studies have demonstrated the potential of plant essential oils to enhance the efficacy of pyrethroids. The toxicity of pyrethroids combined with plant oils is significantly greater than the baseline toxicity of either oils or pyrethroids applied alone, which suggests there are synergistic interactions between components of these mixtures. The present study examined the potential of eight plant essential oils applied in one of two concentrations (1% and 5%) to enhance the toxicity of various pyrethroids (permethrin, natural pyrethrins, deltamethrin and β‐cyfluthrin). The various plant essential oils enhanced the pyrethroids to differing degrees. The levels of enhancement provided by combinations of plant essential oils and pyrethroids in comparison with pyrethroids alone were calculated and synergistic outcomes characterized. Numerous plant essential oils significantly synergized a variety of pyrethroids; type I pyrethroids were synergized to a greater degree than type II pyrethroids. Eight plant essential oils significantly enhanced 24‐h mortality rates provided by permethrin and six plant essential oils enhanced 24‐h mortality rates obtained with natural pyrethrins. By contrast, only three plant essential plants significantly enhanced the toxicity of deltamethrin and β‐cyfluthrin. Of the plant essential oils that enhanced the toxicity of these pyrethroids, some produced varying levels of synergism and antagonism. Geranium, patchouli and Texas cedarwood oils produced the highest levels of synergism, displaying co‐toxicity factors of > 100 in some combinations. To assess the levels of enhancement and synergism of other classes of insecticide, malathion was also applied in combination with the plant oils. Significant antagonism was provided by a majority of the plant essential oils applied in combination with this insecticide, which suggests that plant essential oils may act to inhibit the oxidative activation processes within exposed adult mosquitoes.

With insecticide-resistant mosquito populations becoming an ever-growing concern, new vector control technologies are needed. With the lack of new chemical classes of insecticides to control mosquito populations, the development of novel synergists may improve the performance of available insecticides. We screened a set of 20 plant essential oils alone and in combination with natural pyrethrins against Aedes aegypti (Orlando) female adult mosquitoes to assess their ability to synergize this natural insecticide. A co-toxicity factor analysis was used to identify whether plant oils modulated the toxicity of natural pyrethrins antagonistically, additively, or synergistically. Both knockdown at 1 h and mortality at 24 h were monitored. A majority of oils increased the toxicity of natural pyrethrins, either via an additive or synergistic profile. Many oils produced synergism at 2 µg/insect, whereas others were synergistic only at the higher dose of 10 µg/insect. Amyris, cardamom, cedarwood, and nutmeg East Indies (E.I.) oils were the most active oils for increasing the mortality of natural pyrethrins at 24 h with co-toxicity factors greater than 50 at either or both doses. A number of oils also synergized the 1 h knockdown of natural pyrethrins. Of these, fir needle oil and cypress oils were the most successful at improving the speed-of-action of natural pyrethrins at both doses, with co-toxicity factors of 130 and 62, respectively. To further assess the co-toxicity factor method, we applied selected plant essential oils with variable doses of natural pyrethrins to calculate synergism ratios. Only the oils that produced synergistic co-toxicity factors produced statistically significant synergism ratios. This analysis demonstrated that the degree of co-toxicity factor correlated well with the degree of synergism ratio observed (Pearson correlation coefficient r = 0.94 at 2 µg/insect; r = 0.64 at 10 µg/insect) and that the co-toxicity factor is a useful tool in screening for synergistic activity.

As resistance to the limited number of insecticides available for medical and veterinary pests becomes more widespread, there is an urgent need for new insecticides and synergists on the market. To address this need, we conducted a study to assess the toxicity of three monoterpenoids—carvone, menthone, and fenchone—in comparison to permethrin and methomyl against adults of two common pests: the yellow fever mosquito (Aedes aegypti) and the house fly (Musca domestica). We also examined the potential for these monoterpenoids to enhance the effectiveness of permethrin and methomyl when used together. Finally, we evaluated the ability of each monoterpenoid to inhibit acetylcholinesterase, comparing them to methomyl. While all three monoterpenoids performed relatively poorly as topical insecticides (LD₅₀ > 4000 ng/mg on M. domestica; >6000 ng/mg on Ae. aegypti), they synergized both permethrin and methomyl as well as or better than piperonyl butoxide (PBO). Carvone and menthone yielded synergistic co-toxicity factors (23 and 29, respectively), which were each higher than PBO at 24 h. Currently, the mechanism of action is unknown. During preliminary testing, symptoms of acetylcholinesterase inhibition were identified, prompting further testing. Acetylcholinesterase inhibition did not appear to explain the toxic or synergistic effects of the three monoterpenoids, with IC₅₀ values greater than 1 mM for all, compared to the 2.5 and 1.7 µM for methomyl on Aedes aegypti and Musca domestica, respectively. This study provides valuable monoterpenoid toxicity and synergism data on two pestiferous insects and highlights the potential for these chemistries in future pest control formulations.