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

2021 ◽  
Vol 14 (1) ◽  
Author(s):  
C. L. Moyes ◽  
R. S. Lees ◽  
C. Yunta ◽  
K. J. Walker ◽  
K. Hemmings ◽  
...  
Keyword(s):  
Cytochrome P450 ◽  
Binding Affinity ◽  
Malaria Vector ◽  
Pyrethroid Resistance ◽  
Resistance Mechanisms ◽  
Cross Resistance ◽  
Type I ◽  
Cytochrome P450 Enzymes ◽  
Metabolic Resistance ◽  
The Common

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.

scholarly journals Evaluating the Evidence from Molecular Structure and Population Studies for Cross-Resistance to the Pyrethroids Used in Malaria Vector Control

2020 ◽  
Author(s):  
Catherine L. Moyes ◽  
Rosemary S. Lees ◽  
Cristina Yunta ◽  
Kyle J. Walker ◽  
Kay Hemmings ◽  
...  
Keyword(s):  
Binding Affinity ◽  
Malaria Vector ◽  
Pyrethroid Resistance ◽  
Anopheles Funestus ◽  
Malaria Vectors ◽  
Cross Resistance ◽  
Malaria Vector Control ◽  
Insecticide Treated Nets ◽  
The Common ◽  
The Impact

Abstract 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 Anopheles gambiae s.l. and Anopheles funestus. 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 Aedes aegypti 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.

scholarly journals Evaluating insecticide resistance across African districts to aid malaria control decisions

2020 ◽  
Vol 117 (36) ◽  
pp. 22042-22050 ◽  
Author(s):  
Catherine L. Moyes ◽  
Duncan K. Athinya ◽  
Tara Seethaler ◽  
Katherine E. Battle ◽  
Marianne Sinka ◽  
...  
Keyword(s):  
Cytochrome P450 ◽  
Pyrethroid Resistance ◽  
Resistance Mechanisms ◽  
World Health ◽  
Malaria Vector Control ◽  
Ensemble Model ◽  
Metabolic Resistance ◽  
The World ◽  
Susceptibility Tests ◽  
Health Organization

Malaria vector control may be compromised by resistance to insecticides in vector populations. Actions to mitigate against resistance rely on surveillance using standard susceptibility tests, but there are large gaps in the monitoring data across Africa. Using a published geostatistical ensemble model, we have generated maps that bridge these gaps and consider the likelihood that resistance exceeds recommended thresholds. Our results show that this model provides more accurate next-year predictions than two simpler approaches. We have used the model to generate district-level maps for the probability that pyrethroid resistance inAnopheles gambiaes.l. exceeds the World Health Organization thresholds for susceptibility and confirmed resistance. In addition, we have mapped the three criteria for the deployment of piperonyl butoxide-treated nets that mitigate against the effects of metabolic resistance to pyrethroids. This includes a critical review of the evidence for presence of cytochrome P450-mediated metabolic resistance mechanisms across Africa. The maps for pyrethroid resistance are available on the IR Mapper website, where they can be viewed alongside the latest survey data.

scholarly journals Potential Metabolic Resistance Mechanisms to Ivermectin in Anopheles Gambiae: A Synergist Bioassay Study

2020 ◽  
Author(s):  
Patricia Nicolas ◽  
Caroline Kiuru ◽  
Martin Wagah ◽  
Martha Muturi ◽  
Urs Duthaler ◽  
...  
Keyword(s):  
Cytochrome P450 ◽  
Anopheles Gambiae ◽  
Control Strategies ◽  
Resistance Mechanisms ◽  
World Health ◽  
Malaria Vectors ◽  
Malaria Vector Control ◽  
Cytochrome P450 Enzymes ◽  
Metabolic Resistance ◽  
Active Efflux

Abstract Background Despite remarkable success obtained with current malaria vector control strategies in the last 15 years, additional innovative measures will be needed to achieve the ambitious goals set for 2030 by the World Health Organization (WHO). New tools will need to address insecticide resistance and residual transmission as key challenges. Endectocides such as ivermectin are drugs that kill mosquitoes which feed on treated subjects. Mass administration of ivermectin can effectively target outdoor and early biting vectors, complementing the still effective conventional tools. Although this approach has garnered attention, development of ivermectin resistance is a potential pitfall. Herein, we evaluate the potential role of xenobiotic pumps and cytochrome P450 enzymes in protecting mosquitoes against ivermectin by active efflux and metabolic detoxification, respectively. Methods We determined the lethal-concentration 50 for ivermectin in colonized Anopheles gambiae, then we used chemical inhibitors and inducers of xenobiotic pumps and cytochrome P450 enzymes in combination with ivermectin to probe the mechanism of ivermectin detoxification. Results Dual inhibition of xenobiotic pumps and cytochromes have a synergistic effect with ivermectin, greatly increasing mosquito mortality. Inhibition of xenobiotic pumps alone had no effect on ivermectin-induced mortality. Induction of xenobiotic pumps and cytochromes may confer partial protection from ivermectin.Conclusion there is a clear pathway for development of ivermectin resistance in malaria vectors. Detoxification mechanisms mediated by cytochrome P450 enzymes are more important than xenobiotic pumps in protecting mosquitoes against ivermectin.

scholarly journals A cytochrome P450 allele confers pyrethroid resistance on a major African malaria vector, reducing insecticide-treated bednet efficacy

2019 ◽  
Vol 11 (484) ◽  
pp. eaat7386 ◽  
Author(s):  
Gareth D. Weedall ◽  
Leon M. J. Mugenzi ◽  
Benjamin D. Menze ◽  
Magellan Tchouakui ◽  
Sulaiman S. Ibrahim ◽  
...  
Keyword(s):  
Cytochrome P450 ◽  
Insecticide Resistance ◽  
Malaria Vector ◽  
Southern Africa ◽  
Malaria Control ◽  
Pyrethroid Resistance ◽  
Mosquito Vector ◽  
Metabolic Resistance ◽  
Pyrethroid Insecticides ◽  
The Impact

Metabolic resistance to insecticides such as pyrethroids in mosquito vectors threatens control of malaria in Africa. Unless it is managed, recent gains in reducing malaria transmission could be lost. To improve monitoring and assess the impact of insecticide resistance on malaria control interventions, we elucidated the molecular basis of pyrethroid resistance in the major African malaria vector, Anopheles funestus. We showed that a single cytochrome P450 allele (CYP6P9a_R) in A. funestus reduced the efficacy of insecticide-treated bednets for preventing transmission of malaria in southern Africa. Expression of key insecticide resistance genes was detected in populations of this mosquito vector throughout Africa but varied according to the region. Signatures of selection and adaptive evolutionary traits including structural polymorphisms and cis-regulatory transcription factor binding sites were detected with evidence of selection due to the scale-up of insecticide-treated bednet use. A cis-regulatory polymorphism driving the overexpression of the major resistance gene CYP6P9a allowed us to design a DNA-based assay for cytochrome P450–mediated resistance to pyrethroid insecticides. Using this assay, we tracked the spread of pyrethroid resistance and found that it was almost fixed in mosquitoes from southern Africa but was absent from mosquitoes collected elsewhere in Africa. Furthermore, a field study in experimental huts in Cameroon demonstrated that mosquitoes carrying the resistance CYP6P9a_R allele survived and succeeded in blood feeding more often than did mosquitoes that lacked this allele. Our findings highlight the need to introduce a new generation of insecticide-treated bednets for malaria control that do not rely on pyrethroid insecticides.

scholarly journals Potential metabolic resistance mechanisms to ivermectin in Anopheles gambiae: a synergist bioassay study

2021 ◽  
Vol 14 (1) ◽  
Author(s):  
Patricia Nicolas ◽  
Caroline Kiuru ◽  
Martin G. Wagah ◽  
Martha Muturi ◽  
Urs Duthaler ◽  
...  
Keyword(s):  
Cytochrome P450 ◽  
Anopheles Gambiae ◽  
Control Strategies ◽  
Resistance Mechanisms ◽  
World Health ◽  
Malaria Vectors ◽  
Malaria Vector Control ◽  
Cytochrome P450 Enzymes ◽  
Metabolic Resistance ◽  
Active Efflux

Abstract Background Despite remarkable success obtained with current malaria vector control strategies in the last 15 years, additional innovative measures will be needed to achieve the ambitious goals for malaria control set for 2030 by the World Health Organization (WHO). New tools will need to address insecticide resistance and residual transmission as key challenges. Endectocides such as ivermectin are drugs that kill mosquitoes which feed on treated subjects. Mass administration of ivermectin can effectively target outdoor and early biting vectors, complementing the still effective conventional tools. Although this approach has garnered attention, development of ivermectin resistance is a potential pitfall. Herein, we evaluate the potential role of xenobiotic pumps and cytochrome P450 enzymes in protecting mosquitoes against ivermectin by active efflux and metabolic detoxification, respectively. Methods We determined the lethal concentration 50 for ivermectin in colonized Anopheles gambiae; then we used chemical inhibitors and inducers of xenobiotic pumps and cytochrome P450 enzymes in combination with ivermectin to probe the mechanism of ivermectin detoxification. Results Dual inhibition of xenobiotic pumps and cytochromes was found to have a synergistic effect with ivermectin, greatly increasing mosquito mortality. Inhibition of xenobiotic pumps alone had no effect on ivermectin-induced mortality. Induction of xenobiotic pumps and cytochromes may confer partial protection from ivermectin. Conclusion There is a clear pathway for development of ivermectin resistance in malaria vectors. Detoxification mechanisms mediated by cytochrome P450 enzymes are more important than xenobiotic pumps in protecting mosquitoes against ivermectin.

scholarly journals Escalation of Pyrethroid Resistance in the Malaria Vector Anopheles funestus Induces a Loss of Efficacy of Piperonyl Butoxide–Based Insecticide-Treated Nets in Mozambique

2019 ◽  
Vol 220 (3) ◽  
pp. 467-475 ◽  
Author(s):  
Jacob M Riveron ◽  
Silvie Huijben ◽  
Williams Tchapga ◽  
Magellan Tchouakui ◽  
Murielle J Wondji ◽  
...  
Keyword(s):  
Cytochrome P450 ◽  
Pyrethroid Resistance ◽  
Anopheles Funestus ◽  
Resistance Mechanisms ◽  
Piperonyl Butoxide ◽  
Insecticide Treated Nets ◽  
Molecular Analyses ◽  
Cytochrome P450 Genes ◽  
High Degree ◽  
Long Lasting Insecticidal Nets

Abstract Background Insecticide resistance poses a serious threat to insecticide-based interventions in Africa. There is a fear that resistance escalation could jeopardize malaria control efforts. Monitoring of cases of aggravation of resistance intensity and its impact on the efficacy of control tools is crucial to predict consequences of resistance. Methods The resistance levels of an Anopheles funestus population from Palmeira, southern Mozambique, were characterized and their impact on the efficacy of various insecticide-treated nets established. Results A dramatic loss of efficacy of all long-lasting insecticidal nets (LLINs), including piperonyl butoxide (PBO)–based nets (Olyset Plus), was observed. This An. funestus population consistently (2016, 2017, and 2018) exhibited a high degree of pyrethroid resistance. Molecular analyses revealed that this resistance escalation was associated with a massive overexpression of the duplicated cytochrome P450 genes CYP6P9a and CYP6P9b, and also the fixation of the resistance CYP6P9a_R allele in this population in 2016 (100%) in contrast to 2002 (5%). However, the low recovery of susceptibility after PBO synergist assay suggests that other resistance mechanisms could be involved. Conclusions The loss of efficacy of pyrethroid-based LLINs with and without PBO is a concern for the effectiveness of insecticide-based interventions, and action should be taken to prevent the spread of such super-resistance.

scholarly journals Characterizing Permethrin and Etofenprox Resistance in Two Common Laboratory Strains of Anopheles gambiae (Diptera: Culicidae)

Insects ◽  
2018 ◽  
Vol 9 (4) ◽  
pp. 146 ◽  
Author(s):  
Aaron Gross ◽  
Jeffrey Bloomquist
Keyword(s):  
Anopheles Gambiae ◽  
Pyrethroid Resistance ◽  
Laboratory Strain ◽  
Pyrethroid Insecticide ◽  
Sub Saharan Africa ◽  
Cross Resistance ◽  
Type I ◽  
Mosquito Vector ◽  
Sub Saharan ◽  
Anopheles Gambiae Giles

Anopheles gambiae Giles (Diptera: Culicidae) is the most prolific malaria vector in sub-Saharan Africa, where widespread insecticide resistance has been reported. An. gambiae laboratory strains are commonly used to study the basic biology of this important mosquito vector, and also in new insecticide discovery programs, where insecticide-susceptible and -resistant strains are often used to screen new molecules for potency and cross-resistance, respectively. This study investigated the toxicity of permethrin, a Type-I pyrethroid insecticide, and etofenprox, a non-ester containing pyrethroid insecticide, against An. gambiae at three life stages. This characterization was performed with susceptible (G3; MRA-112) and resistant (Akdr; MRA-1280) An. gambiae strains; the Akdr strain is known to contain the L1014F mutation in the voltage-sensitive sodium channel. Surprisingly, etofenprox displays a lower level of resistance than permethrin against all stages of mosquitoes, except in a headless larval paralysis assay designed to minimize penetration factors. In first-instar An. gambiae larvae, permethrin had significant resistance, determined by the resistance ratio (RR50 = 5), but etofenprox was not significantly different (RR50 = 3.4) from the wild-type strain. Fourth-instar larvae displayed the highest level of resistance for permethrin (RR50 = 108) and etofenprox (RR50 = 35). Permethrin (PC50 = 2 ppb) and etofenprox (PC50 = 9 ppb) resulted in headless larval paralysis (5-h), but resistance, albeit lower, was still present for permethrin (RR50 = 5) and etofenprox (RR50 = 6.9). In adult female mosquitoes, permethrin displayed higher resistance (RR50 = 14) compared to etofenprox (RR50 = 4.3). The level of etofenprox resistance was different from that previously reported for a similar Akron An. gambiae laboratory strain (MRA-913). The chemical synergists piperonyl butoxide (PBO) and diethyl maleate (DEM) were able to synergize permethrin, but not etofenprox in the resistant strain (Akdr). In conclusion, multiple mechanisms are likely involved in pyrethroid resistance, but resistance profiles are dependent upon selection. Etofenprox is an effective insecticide against An. gambiae in the lab but will likely suffer from resistance in the field.

scholarly journals Comparative Study of the Effect of Solvents on the Efficacy of Neonicotinoid Insecticides Against Malaria Vector Populations Across Africa

2022 ◽  
Author(s):  
Magellan Tchouakui ◽  
Tatiane Assatse ◽  
Leon M. J. Mugenzi ◽  
Benjamin D. Menze ◽  
Daniel Nguiffo-Nguete ◽  
...  
Keyword(s):  
Democratic Republic Of Congo ◽  
Natural Populations ◽  
Resistance Mechanisms ◽  
Lower Mortality ◽  
Malaria Vectors ◽  
Cross Resistance ◽  
Metabolic Resistance ◽  
Resistance Development ◽  
Development Of Resistance ◽  
Bottle Test

Abstract Background New insecticides with a novel mode of action such as neonicotinoids have recently been recommended for public health by WHO. Resistance monitoring of such novel insecticides requires a robust protocol to monitor the development of resistance in natural populations. In this study, we comparatively used three different solvents to assess the susceptibility of malaria vectors to neonicotinoids across Africa.MethodsMosquitoes were collected from May to July 2021 from three agricultural settings in Cameroon (Njombe-Penja, Nkolondom, and Mangoum), the Democratic Republic of Congo (Ndjili-Brasserie), Ghana (Obuasi), and Uganda (Mayuge). Using the CDC bottle test, we compared the effect of three different solvents (ethanol, acetone, MERO) on the efficacy of neonicotinoids against Anopheles gambiae s.l. In addition, TaqMan assays were used to genotype key pyrethroid-resistant markers in An. gambiae and to evaluate potential cross-resistance between pyrethroids and clothianidin.ResultsLower mortality were observed when using absolute ethanol or acetone alone as solvent (11.4- 51.9% mortality in Nkolondom, 31.7- 48.2% in Mangoum, 34.6- 56.1% in Mayµge, 39.4- 45.6% in Obuasi, 83.7- 89.3% in Congo and 71.05- 95.9% in Njombe pendja) compared to acetone + MERO for which 100% mortality were observed for all the populations. Synergist assays (PBO, DEM and DEF) revealed a significant increase of mortality suggesting that metabolic resistance mechanisms are contributing to the reduced susceptibility. A negative association was observed between the L1014F-kdr mutation and clothianidin resistance with a greater frequency of homozygote resistant mosquitoes among the dead than among survivors (OR=0.5; P=0.02). However, the I114T-GSTe2 was in contrast significantly associated with a greater ability to survive clothianidin with a higher frequency of homozygote resistant among survivors than other genotypes (OR=2.10; P=0.013). ConclusionsThis study revealed a contrasted susceptibility pattern depending on the solvents with ethanol/acetone resulting to lower mortality, thus possibly overestimating resistance, whereas the MERO consistently showed a greater efficacy of neonicotinoids but it could prevent to detect early resistance development. Therefore, we recommend monitoring the susceptibility using both acetone alone and acetone+MERO (8-10µg/ml for clothianidin) to capture the accurate resistance profile of the mosquito populations.

scholarly journals Widespread Pyrethroid and DDT Resistance in the Major Malaria Vector Anopheles funestus in East Africa Is Driven by Metabolic Resistance Mechanisms

PLoS ONE ◽  
2014 ◽  
Vol 9 (10) ◽  
pp. e110058 ◽  
Author(s):  
Charles Mulamba ◽  
Jacob M. Riveron ◽  
Sulaiman S. Ibrahim ◽  
Helen Irving ◽  
Kayla G. Barnes ◽  
...  
Keyword(s):  
East Africa ◽  
Malaria Vector ◽  
Anopheles Funestus ◽  
Resistance Mechanisms ◽  
Metabolic Resistance ◽  
Ddt Resistance ◽  
Major Malaria Vector

Section 4. Pyrethroid and endosulfan resistance: selection and cross resistance studies

1993 ◽  
Vol 1 ◽  
pp. 28-35 ◽  
Author(s):  
Neil W. Forrester ◽  
Matthew Cahill ◽  
Lisa J. Bird ◽  
Jacquelyn K. Layland
Keyword(s):  
Insecticide Resistance ◽  
Lower Order ◽  
Management Strategy ◽  
Pyrethroid Resistance ◽  
Resistance Management ◽  
Resistance Mechanisms ◽  
Cross Resistance ◽  
Male And Female ◽  
Insecticide Resistance Management ◽  
Resistance Selection

SummaryResistance to endosulfan and pyrethroids in Helicoverpa armigera in Australia was shown to be due to multiple rather than cross resistance. The independence of the endosulfan and pyrethroid resistance mechanisms vindicates the sequential use of these two groups in Stages I and II of the insecticide resistance management strategy, respectively. Within the cyclodienes, greatest resistance occurred to dieldrin with lower order cross resistance to endosulfan and endrin. Male and female moths expressed cyclodiene resistance equally.

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