Mosquito Meets Crystal

Combatting malaria, a disease afflicting more than 250 million people annually according to the World Health Organization (WHO), requires insecticides as part of integrated vector management. Indoor residual spraying (IRS) of crystalline contact insecticides and insecticide-treated bed nets (ITNs) decorated with insecticide crystals are estimated to have reduced malaria mortality in Africa by 60% in the 21st century. However, resistance now threatens malaria control, spurring the development of new insecticides, a process that requires substantial resources, anddiscovery time while posingenvironmental risks. Improving the effectiveness of compounds currently in use may be preferable. This Account provides a brief history of contact insecticides and describes discoveries from our laboratory that suggest paths to faster-acting contact insecticides based on the engineering of solid-state forms, either amorphous or crystalline polymorphs, thereby potentially obviating the need for new chemicals. Contact insecticides are thought to affect insects by absorption through the footpads. Prior to our 2017 report on the structure of a second solid form of DDT, crystal polymorphism was not optimized for contact insecticides. Comparative analysis of knockdown times for flies and mosquitoes against polymorphs of well-known crystalline contact insecticides including DDT and its analogs, as well as lindane, deltamethrin, and imidacloprid, established a link between thermodynamic crystal stability and insect knockdown speed. The relationship between the knockdown by a crystalline contact insecticide and its crystal structure ultimately arises from crystal thermochemistry. Weak intermolecular interactions in complex systems and associated shallow potential energy hypersurfaces readily lead to crystalline polymorphs with different molecular organizations that vary in crystal free energies and associated bioavailabilities. Notably, a new form of deltamethrin was 12 times more active than the commercial form, and the least stable polymorph of imidacloprid was six and nine times more active against susceptible Anopheles and Aedes mosquitoes, respectively, than the commercial, thermodynamically stable form. Some of these metastable polymorphs were found to be stable against transformation to their thermodynamically stable forms for months in an idealized laboratory setting, approaching WHO guidelines for practical use. The observation of differing polymorph effectiveness demonstrates that tarsal absorption of molecules from the crystal surfaces by insects is a key step, and likely a limiting step, in the insecticidal action. Indeed, a persistently amorphous form of deltamethrin dispersed on chalk exhibited dramatically increased efficacy against deltamethrin-resistant Anopheles mosquitoes from Burkina Faso, revealing that an increased rate of insecticide uptake overwhelmed all the resistance mechanisms tested. Collectively, this work argues that manipulation of the solid-state chemistry of contact insecticides is a viable strategy for mitigating insect-borne diseases and one that should be considered along with others in integrated vector management.