Cross-resistance profiles of malaria mosquito P450s associated with pyrethroid resistance against WHO insecticides

Yunta, Cristina; Hemmings, Kay; Stevenson, Bradley J.; Koekemoer, Lizette L.; Matambo, Tonderi; Pignatelli, Patricia; Voice, Michael W.; Nász, Szilárd; Paine, Mark J. I.

doi:10.1016/j.pestbp.2019.06.007

Cited by 96 publications

(113 citation statements)

References 36 publications

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“…There is evidence that some mechanisms of pyrethroid resistance differ in the level of resistance they confer to different compounds; for example, different depletion rates were found across 6 pyrethroid compounds when they were metabolised by 8 Anopheles cytochrome P450 enzymes under controlled conditions [52]. These differences have not been investigated for all mechanisms of resistance, and there is no evidence that the differences seen for individual resistance mechanisms tested in the laboratory translate into diverging patterns of resistance in the field.…”

Section: Plos Biologymentioning

confidence: 99%

Mapping trends in insecticide resistance phenotypes in African malaria vectors

et al. 2020

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Mitigating the threat of insecticide resistance in African malaria vector populations requires comprehensive information about where resistance occurs, to what degree, and how this has changed over time. Estimating these trends is complicated by the sparse, heterogeneous distribution of observations of resistance phenotypes in field populations. We use 6,423 observations of the prevalence of resistance to the most important vector control insecticides to inform a Bayesian geostatistical ensemble modelling approach, generating fine-scale predictive maps of resistance phenotypes in mosquitoes from the Anopheles gambiae complex across Africa. Our models are informed by a suite of 111 predictor variables describing potential drivers of selection for resistance. Our maps show alarming increases in the prevalence of resistance to pyrethroids and DDT across sub-Saharan Africa from 2005 to 2017, with mean mortality following insecticide exposure declining from almost 100% to less than 30% in some areas, as well as substantial spatial variation in resistance trends.

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Section: Plos Biologymentioning

confidence: 99%

Mapping trends in insecticide resistance phenotypes in African malaria vectors

et al. 2020

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“…We observed a minimal interference from these insecticide resistance mechanisms on the effectiveness of MET, suggesting that a MET-based field-intervention could be effective in areas where conventional insecticides have reduced effectiveness. The juvenile hormone agonist, pyriproxyfen, is a more potent inhibitor of P450 enzymes (Yunta et al, 2019(Yunta et al, , 2016 and, direct metabolism of PPF by P450s has been demonstrated in vitro and associated with a moderate level of PPF resistance in vivo (Yunta et al, 2016). The results of the current study provide encouragement that the 20E agonist, MET, would be active against a wide range of field populations and may have reduced resistance liabilities compared to PPF.…”

Section: Discussionmentioning

confidence: 58%

“…Competitive binding assays with MET and the fluorescent molecule diethoxyfluorescein (DEF) were carried out as previously described (Yunta et al, 2019) using the identical enzyme batch used in published studies evaluating binding of other public health insecticides (Yunta et al, 2019). Methoxyfenozide concentrations ranged from 0.0013µM to 2000µM final concentration; control wells contained DEF only.…”

Section: Cytochrome P450 Competitive Binding Assaysmentioning

confidence: 99%

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Steroid hormone agonists reduce female fitness in insecticide-resistantAnophelespopulations

Brown

Paton

Catteruccia

et al. 2020

Preprint

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AbstractInsecticide based vector control tools such as insecticide treated bednets and indoor residual spraying represent the cornerstones of malaria control programs. Resistance to chemistries used in these programs is now widespread and represents a significant threat to the gains seen in reducing malaria-related morbidity and mortality. Recently, disruption of the 20-hydroxyecdysone steroid hormone pathway was shown to reduce Plasmodium development time and significantly reduce both longevity and egg production in a laboratory susceptible Anopheles gambiae population. Here, we demonstrate that disruption of this pathway by application of methoxyfenozide (MET) to insecticide resistant An. coluzzii, An. gambiae sl and An. funestus populations significantly reduces egg production in both topical and tarsal application. Moreover, MET reduces adult longevity when applied topically, and tarsally after blood feeding. As the cytochrome p450s elevated in pyrethroid resistant Anopheles only bind MET very weakly, this compound is unlikely to be subject to cross-resistance in a field-based setting. Manipulation of this hormonal signalling pathway therefore represents a potential complementary approach to current malaria control strategies, particularly in areas where high levels of insecticide resistance are compromising existing tools.

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“…Many African populations of adult Anopheline mosquitoes express elevated levels of P450 activity associated with metabolic co-resistance to pyrethroids 19 and other insecticide classes. Since P450s can metabolise a wide range of chemical substrates these pose a pre-eminent cross-resistance liability for new chemistries introduced into the insect control market 20,21 . An.…”

mentioning

confidence: 99%

New insecticide screening platforms indicate that Mitochondrial Complex I inhibitors are susceptible to cross-resistance by mosquito P450s that metabolise pyrethroids

Lees

Ismail

Logan

et al. 2020

Sci Rep

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Fenazaquin, pyridaben, tolfenpyrad and fenpyroximate are Complex I inhibitors offering a new mode of action for insecticidal malaria vector control. However, extended exposure to pyrethroid based products such as long-lasting insecticidal nets (LLINs) has created mosquito populations that are largely pyrethroid-resistant, often with elevated levels of P450s that can metabolise and neutralise diverse substrates. To assess cross-resistance liabilities of the Complex I inhibitors, we profiled their susceptibility to metabolism by P450s associated with pyrethroid resistance in Anopheles gambiae (CYPs 6M2, 6P3, 6P4, 6P5, 9J5, 9K1, 6Z2) and An. funestus (CYP6P9a). All compounds were highly susceptible. Transgenic An. gambiae overexpressing CYP6M2 or CYP6P3 showed reduced mortality when exposed to fenpyroximate and tolfenpyrad. Mortality from fenpyroximate was also reduced in pyrethroid-resistant strains of An. gambiae (VK7 2014 and Tiassalé 13) and An. funestus (FUMOZ-R). P450 inhibitor piperonyl butoxide (PBO) significantly enhanced the efficacy of fenpyroximate and tolfenpyrad, fully restoring mortality in fenpyroximate-exposed FUMOZ-R. Overall, results suggest that in vivo and in vitro assays are a useful guide in the development of new vector control products, and that the Complex I inhibitors tested are susceptible to metabolic cross-resistance and may lack efficacy in controlling pyrethroid resistant mosquitoes.

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Cross-resistance profiles of malaria mosquito P450s associated with pyrethroid resistance against WHO insecticides

Cited by 96 publications

References 36 publications

Mapping trends in insecticide resistance phenotypes in African malaria vectors

Mapping trends in insecticide resistance phenotypes in African malaria vectors

Steroid hormone agonists reduce female fitness in insecticide-resistantAnophelespopulations

New insecticide screening platforms indicate that Mitochondrial Complex I inhibitors are susceptible to cross-resistance by mosquito P450s that metabolise pyrethroids

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