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<jats:title>Abstract</jats:title> <jats:p>The primary malaria control intervention in high burden countries is the deployment of long-lasting insecticide-treated nets (LLINs) treated with pyrethroids, alone or in combination with a second active ingredient or synergist. It is essential to understand whether the impact of pyrethroid resistance can be mitigated by switching between different pyrethroids or whether cross-resistance precludes this. Structural diversity within the pyrethroids could mean some compounds are better able to counteract the resistance mechanisms that have evolved in malaria vectors. Here we consider variation in vulnerability to the P450 enzymes that confer metabolic pyrethroid resistance in <jats:italic>Anopheles gambiae</jats:italic> s.l. and <jats:italic>Anopheles funestus. </jats:italic>We assess the relationships among pyrethroids in terms of their binding affinity to key P450s and the percent dep­letion by these P450s, in order to identify which pyrethroids diverge from the others. We then investigate whether these same pyrethroids also diverge from the others in terms of resistance in vector populations. We found that etofenprox, which lacks the common structural moiety of other pyrethroids, potentially diverges from the commonly deployed pyrethroids in terms of P450 binding affinity and resistance in malaria vector populations, but not depletion by the P450s tested. These results are supplemented by an analysis of resistance to the same pyrethroids in <jats:italic>Aedes aegypti</jats:italic> populations, which also found etofenprox diverges from the other pyrethroids in terms of resistance in wild populations. In addition, we found that bifenthrin, which also lacks the common structural moiety of most pyrethroids, diverges from the commonly deployed pyrethroids in terms of P450 binding affinity and depletion by P450s. However, resistance to bifenthrin in vector populations is largely untested. The prevalence of resistance to the pyrethroids α-cypermethrin, cyfluthrin, deltamethrin, λ-cyhalothrin, and permethrin was correlated across malaria vector populations and switching between these compounds as a tool to mitigate against pyrethroid resistance is not advised without strong evidence supporting a true difference in resistance.</jats:p>

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