Pyrethroid contact insecticides are mainstays of malaria control, but their efficacies are declining due to widespread insecticide resistance in Anopheles mosquito populations, a major public health challenge. Several strategies have been proposed to overcome this challenge, including insecticides with new modes of action. New insecticides, however, can be expensive to implement in low-income countries. Here, we report a simple and inexpensive method to improve the efficacy of deltamethrin, the most active and most commonly used pyrethroid, by more than 10 times against Anopheles mosquitoes. Upon heating for only a few minutes, the commercially available deltamethrin crystals, form I, melt and crystallize upon cooling into a polymorph, form II, which is much faster acting against fruit flies and mosquitoes. Epidemiological modeling suggests that the use of form II in indoor residual spraying in place of form I would significantly suppress malaria transmission, even in the presence of high levels of resistance. The simple preparation of form II, coupled with its kinetic stability and markedly higher efficacy, argues that form II can provide a powerful, timely, and affordable malaria control solution for low-income countries that are losing protection in the face of worldwide pyrethroid resistance.
Imidacloprid, the world’s leading insecticide, has been approved recently for controlling infectious disease vectors; yet, in agricultural settings, it has been implicated in the frightening decline of pollinators. This argues for strategies that sharply reduce the environmental impact of imidacloprid. When used as a contact insecticide, the effectiveness of imidacloprid relies on physical contact between its crystal surfaces and insect tarsi. Herein, seven new imidacloprid crystal polymorphs are reported, adding to two known forms. Anticipating that insect uptake of imidacloprid molecules would depend on the respective free energies of crystal polymorph surfaces, measurements of insect knockdown times for the metastable crystal forms were as much as nine times faster acting than the commercial form against Aedes, Anopheles, and Culex mosquitoes as well as Drosophila (fruit flies). These results suggest that replacement of commercially available imidacloprid crystals (a.k.a. Form I) in space-spraying with any one of three new polymorphs, Forms IV, VI, IX, would suppress vector-borne disease transmission while reducing environmental exposure and harm to nontarget organisms.
The sensitivity of longitudinal magnetization and singlet order to relaxation from dissolved paramagnetic oxygen sources in solution is investigated experimentally.
The active forms of contact insecticides used for combatting mosquito-borne infectious diseases are typically crystalline solids. Numerous molecular crystals are polymorphic, crystallizing in several solid forms characterized by different physicochemical properties, including bioavailability. Our laboratory recently found that the activity of crystalline contact insecticides is inversely dependent on the thermodynamic stability of their polymorphs, suggesting that efficacy can be enhanced by the manipulation of the solid-state structure. This paper argues that crystallography should be central to the development of contact insecticides, particularly because their efficacy continues to be compromised by insecticide resistance, especially among Anopheles mosquito populations that spread malaria. Although insecticidal compounds with new modes of action have been introduced to overcome resistance, new insecticides are expensive to develop and implement. The repurposing of existing chemical agents in metastable, more active crystalline forms provides an inexpensive and efficient method for ‘evergreening’ compounds whose risks are already well-established. We report herein seven new single-crystal structures of insecticides used for controlling infectious disease vectors. The structures reported herein include pyrethroid insecticides recommended by the WHO for indoor residual spraying (IRS)-bifenthrin, β-cyfluthrin, etofenprox, α-cypermethrin, and λ-cyhalothrin as well as the neonicotinoid insecticide thiacloprid.
Background Controlling malaria-transmitting Anopheles mosquitoes with pyrethroid insecticides is becoming increasingly challenging because of widespread resistance amongst vector populations. The development of new insecticides and insecticidal formulations is time consuming and costly, however. A more active crystalline form of deltamethrin, prepared by heating the commercial crystalline form, previously was reported to be 12-times faster acting against susceptible North American Anopheles quadrimaculatus mosquitoes. Herein the potential for heat-activated deltamethrin dispersed on chalk to overcome various resistance mechanisms amongst five West African Anopheles strains is investigated, and its long-term sustained lethality evaluated. Methods The more active deltamethrin form was generated in a commercial dust containing deltamethrin by heating the material as purchased. Tarsal contact bioassays were conducted to investigate its efficacy, potency, and speed of action against resistant Anopheles populations compared to the commercially available form of deltamethrin dust. Results In all cases, D-Fense Dust heated to generate the more active form of deltamethrin was substantially more effective than the commercially available formulation. 100% of both Banfora M and Kisumu populations were knocked down 10 min post-exposure with no recovery afterwards. Gaoua-ara and Tiefora strains exhibited 100% knockdown within 15 min, and the VK7 2014 strain exhibited 100% knockdown within 20 min. In all cases, 100% mortality was observed 24 h post-exposure. Conversely, the commercial formulation (unheated) resulted in less than 4% mortality amongst VK7 2014, Banfora, and Gaoua-ara populations by 24 h, and Tiefora and Kisumu mosquitoes experienced 14 and 47% mortality by 24 h, respectively. The heat-activated dust maintained comparable efficacy 13 months after heating. Conclusions The heat-activated form of commercial deltamethrin D-Fense Dust outperformed the material as purchased, dramatically increasing efficacy against all tested pyrethroid-resistant strains. This increase in lethality was retained for 13 months of storage under ambient conditions in the laboratory. Higher energy forms of commonly used insecticides may be employed to overcome various resistance mechanisms seen in African Anopheles mosquitoes through more rapid uptake of insecticide molecules from their respective solid surfaces. That is, resistant mosquitoes can be killed with an insecticide to which they are resistant without altering the molecular composition of the insecticide.
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