Assessing cross-resistance within the pyrethroids in terms of their interactions with key cytochrome P450 enzymes and resistance in vector populations

Abstract

Background It is important to understand whether the potential impact of pyrethroid resistance on malaria control can be mitigated by switching between different pyrethroids or whether cross-resistance within this insecticide class precludes this approach. Methods Here we assess the relationships among pyrethroids in terms of their binding affinity to, and depletion by, key cytochrome P450 enzymes (hereafter P450s) that are known to confer metabolic pyrethroid resistance in Anopheles gambiae (s.l.) and An. funestus, in order to identify which pyrethroids may diverge from the others in their vulnerability to resistance. We then investigate whether these same pyrethroids also diverge from the others in terms of resistance in vector populations. Results We found that the type I and II pyrethroids permethrin and deltamethrin, respectively, are closely related in terms of binding affinity to key P450s, depletion by P450s and resistance within vector populations. Bifenthrin, which lacks the common structural moiety of most pyrethroids, diverged from the other pyrethroids tested in terms of both binding affinity to key P450s and depletion by P450s, but resistance to bifenthrin has rarely been tested in vector populations and was not analysed here. Etofenprox, which also lacks the common structural moiety of most pyrethroids, diverged from the more commonly deployed pyrethroids in terms of binding affinity to key P450s and resistance in vector populations, but did not diverge from these pyrethroids in terms of depletion by the P450s. The analysis of depletion by the P450s indicated that etofenprox may be more vulnerable to metabolic resistance mechanisms in vector populations. In addition, greater resistance to etofenprox was found across Aedes aegypti populations, but greater resistance to this compound was not found in any of the malaria vector species analysed. The results for pyrethroid depletion by anopheline P450s in the laboratory were largely not repeated in the findings for resistance in malaria vector populations. Conclusion Importantly, 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.

Review and Meta-Analysis of the Evidence for Choosing between Specific Pyrethroids for Programmatic Purposes

“…Molecular studies indicate that structurally diverse pyrethroids such as tefluthrin, transfluthrin, bifenthrin, and etofenprox, which lack the common structural moiety of most pyrethroids, may interact differently with the common resistance mechanisms found in insect populations [ 11 , 12 , 13 ] ( Figure 2 ). To assess cross-resistance within the pyrethroids in terms of their interactions with key cytochrome P450 enzymes (hereafter P450s) and resistance in vector populations, P450 functional activity data with pyrethroids were compared with field mortality data [ 12 ]. Figure 3 shows the relationships among pyrethroids in terms of their binding affinity to and depletion by key P450 enzymes known to confer metabolic pyrethroid resistance in Anopheles gambiae (s.l.)…”

“…in comparison to mortality data among pyrethroids. Bifenthrin diverges from the pyrethroids commonly used in malaria vector control in terms of binding affinity to, and depletion by, P450s from African Anopheles species, while etofenprox diverges from the other pyrethroids in terms of binding affinity to these P450s, but not depletion by them [ 12 ]. When these relative differences found by molecular studies were compared to relative differences in the prevalence of resistance to each pyrethroid within African malaria vector populations, the potential divergence of etofenprox was observed in both the molecular studies and the field studies, but bifenthrin has not yet been tested in field studies of African malaria vectors ( Figure 3 ).…”

“…The dendrograms were constructed using correlations in mortality across African malaria vector populations (Pearson’s correlation coefficient) ( A ), binding affinity values (IC50), ( B ) and insecticide depletion values (%) ( C ). Adapted from [ 12 ].…”

Review and Meta-Analysis of the Evidence for Choosing Between Specific Pyrethroids for Programmatic Purposes.

“…Molecular studies indicate that structurally diverse pyrethroids such as tefluthrin, transfluthrin, bifenthrin and etofenprox that lack the common structural moiety of most pyrethroids may interact differently to the common resistance mechanisms found in insect populations [10]- [12] (Figure ). Bifenthrin diverges from the pyrethroids commonly used in malaria vector control in terms of binding affinity to, and depletion by, P450s from African Anopheles species, while etofenprox diverges from the other pyrethroids in terms of binding affinity to these P450s but not depletion by them [11]. When these relative differences found by molecular studies were compared to relative differences in the prevalence of resistance to each pyrethroid within African malaria vector populations, the potential divergence of etofenprox was observed in both the molecular studies and the field studies but bifenthrin has not yet been tested in field studies of African malaria vectors (Figure 3).…”

“…The common scaffold of pyrethroids, boxed in red, was identified by searching 230 million compounds available in the ZINC database (https ://zinc.docki ng.org). Adapted from [11].…”