A deltamethrin crystal polymorph for more effective malaria control

Abstract

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.

Keywords: deltamethrin; epidemiological modeling; malaria; mosquito; polymorphism.

Fig. 1.

(A) Molecular structure of DM. (B) Microcrystals in suspension concentrate (Suspend SC, DM concentration: 5%), a formulation used for IRS. (C and D) Melt grown DM (C) form I and (D) form II spherulites observed between crossed polarizers. PXRD confirmed that the fibers in the spherulite were oriented along the crystallographic <010> direction. (E) PXRD data for form I (blue) and form II (orange) from their respective films. (F and G) Single crystal structures of forms (F) I (12) and (G) II determined at 100 K.

Fig. 2.

Lethality comparison of DM forms I and II against D. melanogaster. (A) Experimental setup for lethality comparisons using crystalline films of DM form I or II covered with microislands of PEG (sprayed on films to reduce their activity so that the KTs could be compared more readily), schematically illustrated by the blue dots in the side view and revealed in scanning electron micrographs. At higher magnification (10-mm scale bar), form II crystallites were observed between PEG islands. (B) The motions of D. melanogaster exposed to crystalline films. The dots represent the average speed of all fruit flies in 1 min, smoothed (solid line) by a Savitzky−Golay filter. (C) KTs for D. melanogaster exposed to crystalline films. KT₅₀ values are indicated, as in F. (D) Setup for lethality comparisons of dusts. Form I dust was converted to form II dust by heating, either using a microwave oven or convective heating (SI Appendix, Fig. S5). (E) Motions of D. melanogaster exposed to dusts. (F) KTs for D. melanogaster exposed to dusts.

Fig. 3.

Lethality of DM crystalline forms I and II against A. aegypti and A. quadrimaculatus mosquitoes. (A) The motions of A. aegypti mosquitoes exposed to dusts. The dots represent the average speed of all mosquitoes in 1 min. Solid lines are smoothed trend lines (as in C), See also SI Appendix, Fig. S6. (B) Comparison of A. aegypti KTs for forms I and II dusts. KT₅₀ values are indicated, as in D. (C) Motions of A. quadrimaculatus mosquitoes exposed to dusts. (D) Comparison of A. quadrimaculatus KTs using dusts.

Fig. 4.

Simulation of malaria transmission dynamics. (A) Effectiveness of IRS for inhibition of malaria transmission, using the same doses of DM form I (Left) or II (Right) at varying levels of coverage and insecticide resistance with an initial human infection prevalence of 45%. Insecticide resistance corresponds to the percentage of mosquitoes that survive after contacting the applied dose of form I. Coverage corresponds to the probability of a mosquito contacting the insecticide during a single resting episode. (B) Predicted reduction in population of infected mosquitoes and human prevalence upon application of DM form I and then switching to form II (coverage = 75%; resistance = 70%; infection prevalence = 45%, denoted in Fig. 4A as red squares). Both the population of infected mosquitoes and human disease prevalence dropped precipitously.