Pyriproxyfen is metabolized by P450s associated with pyrethroid resistance in An. gambiae

Abstract

Pyrethroid resistance is widespread in the malaria vector Anopheles gambiae leading to concerns about the future efficacy of bednets with pyrethroids as the sole active ingredient. The incorporation of pyriproxyfen (PPF), a juvenile hormone analogue, into pyrethroid treated bednets is being trialed in Africa. Pyrethroid resistance is commonly associated with elevated levels of P450 expression including CYPs 6M2, 6P2, 6P3, 6P4, 6P5, 6Z2 and 9J5. Having expressed these P450s in E. coli we find all are capable of metabolizing PPF. Inhibition of these P450s by permethrin, deltamethrin and PPF was also examined. Deltamethrin and permethrin were moderate inhibitors (IC 1-10 μM) of diethoxyfluorescein (DEF) activity for all P450s apart from CYP6Z2 (IC > 10 μM), while PPF displayed weaker inhibition of all P450s (IC > 10 μM) except CYP's 6Z2 and 6P2 (IC 1-10 μM). We found evidence of low levels of cross resistance between PPF and other insecticide classes by comparing the efficacy of PPF in inhibiting metamorphosis and inducing female sterility in an insecticide susceptible strain of An. gambiae and a multiple resistant strain from Cote d'Ivoire.

Deltamethrin is metabolized by CYP6FU1, a cytochrome P450 associated with pyrethroid resistance, in Laodelphax striatellus

“…CYP6FU1 belongs to the CYP6 family. Several CYP genes belonging to this family have been found to catalyze the oxidative metabolism of pyrethroids in various insects, such as CYP6M2 in Anopheles gambiae , CYP6BQ23 in Meligethes aeneus and CYP genes 6 M2 , 6P2 , 6P3 , 6P4 , 6P5 and 6Z2 in A. gambiae . Furthermore, some genes belonging to subfamily CYP6F have been studied using RNA interference (RNAi), and the results suggest that they detoxify deltamethrin in Locusta migratoria .…”

“…Several CYP genes belonging to this family have been found to catalyze the oxidative metabolism of pyrethroids in various insects, such as CYP6M2 in Anopheles gambiae, 26 CYP6BQ23 in Meligethes aeneus and CYP genes 6 M2, 6P2, 6P3, 6P4, 6P5 and 6Z2 in A. gambiae. 27,28 Furthermore, some genes belonging to subfamily CYP6F have been studied using RNA interference (RNAi), and the results suggest that they detoxify deltamethrin in Locusta migratoria. 29 The findings of the present study confirming the role of over-expressed CYP6FU1 in deltamethrin resistance in L. striatellus are thus in accordance with the results of previous studies.…”

Truck‐mounted area‐wide applications of larvicides and adulticides for extended suppression of adult Aedes albopictus

“…Although no resistance to pyriproxyfen was detected in New Jersey populations, significant but low resistance to pyriproxyfen was found in Florida and a recent study showed that pyriproxyfen is metabolized by P450s (detoxification enzymes) associated with pyrethroid resistance in An. gambiae . If this insecticide is to be used in future in the USA, constant monitoring of the insecticide resistance status of Aedes populations is recommended.…”

“…gambiae. 54 If this insecticide is to be used in future in the USA, constant monitoring of the insecticide resistance status of Aedes populations is recommended.…”

Steroid hormone agonists reduce female fitness in insecticide-resistantAnophelespopulations

“…Mathematical models demonstrate that these new classes of nets could play a key role in reducing malaria cases in areas with high levels of insecticide resistance (Churcher et al, 2016). Nevertheless, there is a continual need for innovation into new LLINs, to pre-empt future resistance challenges; indeed there are already reports of cross resistance between pyrethroids and pyriproxyfen which may undermine the performance of these dual action nets in some settings (Yunta et al, 2016).…”