Indoor residual spraying of insecticides has been a widely used strategy for malaria control and has helped eliminate malaria as a public health threat from many areas. In recent years, insecticide treated bed nets (ITNs) have been recognized as a cheap and effective tool to control the spread of malaria. However, a major challenge efforts to eradicate malaria face is the evolution of insecticide resistance in Anopheles mosquito populations, driven by spraying of insecticides. It is alarming to note that spraying has been observed to drive insecticide-resistant Anopheles populations from zero to 20% in a period as short as three years, especially when resistance alleles are present in the mosquito population. With use of ITNs, there is concern that similar resistance may rapidly evolve and efforts to control malaria may be rendered ineffective. In a recent article¹, Read et al discuss strategies for development of evolution-proof insecticides for controlling the spread of malaria. The authors point out that the solution to the problem of countering resistance does not lie in development of new insecticides, because all existing insecticides were “new” at some point. Instead they suggest that late-life acting (LLA) insecticides may provide an evolution-proof strategy and help maintain low transmission rates while minimizing selection for resistance.

Conventional insecticides (such as DDT, malathion and pyrethroid) are fast-acting and very effective in the short-term (reducing infectious bites by upto 99.8%), however, they kill young female adult mosquitoes and impose a large selection pressure for resistance evolution. By modeling the evolution of insecticide resistance, the authors show that resistance spreads more slowly for LLA insecticides than for conventional ones. Conventional insecticides that kill on first contact reduce mosquito lifetime reproductive success by ~85% (hence, mutant resistant mosquitoes are about 6.5 times more fit than the wild-type). On the other hand, LLA insecticides that kill mosquitoes that have reached at least their fourth feeding-egg laying cycle will eliminate only 22% of their progeny (hence resistant mosquitoes are only about 1.3 times more fit than the wild type—a much lowered resistance benefit than in the case of conventional insecticides). Thus, in a situation where the resistance benefit is outweighed by the cost of resistance, resistance will not spread, even when resistance alleles are present in the population.

How does one design LLA insecticides? Read et al suggest formulation techniques such as microencapsulation that would slowly release the insecticide over time. Alternatively, they suggest use of fungal biopesticides that have shown promise in the laboratory, or use of sub-lethal doses over multiple feeding cycles that would affect only older mosquitoes. The WHO, in determining which insecticides to recommend to various national authorities, currently uses a threshold of 80% mortality up to 24h post-exposure in young adult Anopheles. If the threshold is lowered, it is possible that some of the slower-acting insecticides rejected in previous screens may turn out to be effective as LLA agents.

The Global Malaria Action Plan aims to cover 172 million houses annually by spraying and distribute 730 million ITNs by 2010. Given the past record of emergence of insecticide-resistant Anopheles, it is likely that, if only existing insecticides are used, major undertakings like that of the GMAP will impose high selective pressures for resistance and will ultimately not be effective in controlling malaria in the long term. Using LLA insecticides, instead, could circumvent the problem of insecticide resistance and help the GMAP maintain vector control as a key tool in the effort to eradicate malaria.

1. Read, A.F., Lynch, P.A., Thomas, M.B. (2009) PLoS Biology 7(4):e1000058 doi:10.1371/journal.pbio.1000058