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The Cytochrome P450 gene CYP6P12 confers pyrethroid resistance in kdr-free Malaysian populations of the dengue vector Aedes albopictus.

Ishak IH, Riveron JM, Ibrahim SS, Stott R, Longbottom J, Irving H, Wondji CS - Sci Rep (2016)

Bottom Line: Microarray-based transcription profiling revealed that metabolic resistance (cytochrome P450 up-regulation) and possibly a reduced penetration mechanism (consistent over-expression of cuticular protein genes) were associated with pyrethroid resistance.CYP6P12 over-expression was strongly associated with pyrethroid resistance whereas CYP6N3 was rather consistently over-expressed across carbamate and DDT resistant populations.The major role played by P450 in the absence of kdr mutations suggests that addition of the synergist PBO to pyrethroids could improve the efficacy of this insecticide class and overcome resistance in field populations of Ae. albopictus.

View Article: PubMed Central - PubMed

Affiliation: Department of Vector Biology, Liverpool School of Tropical Medicine, Pembroke Place, Liverpool L3 5QA, United Kingdom.

ABSTRACT
Control of Aedes albopictus, major dengue and chikungunya vector, is threatened by growing cases of insecticide resistance. The mechanisms driving this resistance remain poorly characterised. This study investigated the molecular basis of insecticide resistance in Malaysian populations of Ae. albopictus. Microarray-based transcription profiling revealed that metabolic resistance (cytochrome P450 up-regulation) and possibly a reduced penetration mechanism (consistent over-expression of cuticular protein genes) were associated with pyrethroid resistance. CYP6P12 over-expression was strongly associated with pyrethroid resistance whereas CYP6N3 was rather consistently over-expressed across carbamate and DDT resistant populations. Other detoxification genes also up-regulated in permethrin resistant mosquitoes included a glucuronosyltransferase (AAEL014279-RA) and the glutathione-S transferases GSTS1 and GSTT3. Functional analyses further supported that CYP6P12 contributes to pyrethroid resistance in Ae. albopictus as transgenic expression of CYP6P12 in Drosophila was sufficient to confer pyrethroid resistance in these flies. Furthermore, molecular docking simulations predicted CYP6P12 possessing enzymatic activity towards pyrethroids. Patterns of polymorphism suggested early sign of selection acting on CYP6P12 but not on CYP6N3. The major role played by P450 in the absence of kdr mutations suggests that addition of the synergist PBO to pyrethroids could improve the efficacy of this insecticide class and overcome resistance in field populations of Ae. albopictus.

No MeSH data available.


Related in: MedlinePlus

Binding conformation of (a) permethrin, (b) deltamethrin, (c) bendiocarb, and (d) DDT in the active site of CYP6P12. CYP6P12 is presented in helices and cyan in colour. Heme is in stick format and grey. Distances between insecticides and heme iron are annotated.
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f5: Binding conformation of (a) permethrin, (b) deltamethrin, (c) bendiocarb, and (d) DDT in the active site of CYP6P12. CYP6P12 is presented in helices and cyan in colour. Heme is in stick format and grey. Distances between insecticides and heme iron are annotated.

Mentions: Docking parameters for all insecticide ligands screened are provided in Table S8. Overall, CYP6P12 produced good binding score for all pyrethroids screened, as well as DDT and bendiocarb. However, analysis of the binding conformation revealed that though pyrethroids bind productively in the active site of the enzyme, the sites of hydroxylation were not the 4′ spot established as the most preferred by the insect P450s. For example, permethrin binds with the 6 position of the benzyl ring oriented above the heme and within 5.2 Å from the heme iron, while deltamethrin binds with the 2′ spot of the phenoxy ring oriented for hydroxylation at a distance of 4.5 Å (Fig. 5a,b respectively). The 4′ phenoxy ring has been established as the most preferred site of hydroxylation of pyrethroids by insect P4502223.


The Cytochrome P450 gene CYP6P12 confers pyrethroid resistance in kdr-free Malaysian populations of the dengue vector Aedes albopictus.

Ishak IH, Riveron JM, Ibrahim SS, Stott R, Longbottom J, Irving H, Wondji CS - Sci Rep (2016)

Binding conformation of (a) permethrin, (b) deltamethrin, (c) bendiocarb, and (d) DDT in the active site of CYP6P12. CYP6P12 is presented in helices and cyan in colour. Heme is in stick format and grey. Distances between insecticides and heme iron are annotated.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4837359&req=5

f5: Binding conformation of (a) permethrin, (b) deltamethrin, (c) bendiocarb, and (d) DDT in the active site of CYP6P12. CYP6P12 is presented in helices and cyan in colour. Heme is in stick format and grey. Distances between insecticides and heme iron are annotated.
Mentions: Docking parameters for all insecticide ligands screened are provided in Table S8. Overall, CYP6P12 produced good binding score for all pyrethroids screened, as well as DDT and bendiocarb. However, analysis of the binding conformation revealed that though pyrethroids bind productively in the active site of the enzyme, the sites of hydroxylation were not the 4′ spot established as the most preferred by the insect P450s. For example, permethrin binds with the 6 position of the benzyl ring oriented above the heme and within 5.2 Å from the heme iron, while deltamethrin binds with the 2′ spot of the phenoxy ring oriented for hydroxylation at a distance of 4.5 Å (Fig. 5a,b respectively). The 4′ phenoxy ring has been established as the most preferred site of hydroxylation of pyrethroids by insect P4502223.

Bottom Line: Microarray-based transcription profiling revealed that metabolic resistance (cytochrome P450 up-regulation) and possibly a reduced penetration mechanism (consistent over-expression of cuticular protein genes) were associated with pyrethroid resistance.CYP6P12 over-expression was strongly associated with pyrethroid resistance whereas CYP6N3 was rather consistently over-expressed across carbamate and DDT resistant populations.The major role played by P450 in the absence of kdr mutations suggests that addition of the synergist PBO to pyrethroids could improve the efficacy of this insecticide class and overcome resistance in field populations of Ae. albopictus.

View Article: PubMed Central - PubMed

Affiliation: Department of Vector Biology, Liverpool School of Tropical Medicine, Pembroke Place, Liverpool L3 5QA, United Kingdom.

ABSTRACT
Control of Aedes albopictus, major dengue and chikungunya vector, is threatened by growing cases of insecticide resistance. The mechanisms driving this resistance remain poorly characterised. This study investigated the molecular basis of insecticide resistance in Malaysian populations of Ae. albopictus. Microarray-based transcription profiling revealed that metabolic resistance (cytochrome P450 up-regulation) and possibly a reduced penetration mechanism (consistent over-expression of cuticular protein genes) were associated with pyrethroid resistance. CYP6P12 over-expression was strongly associated with pyrethroid resistance whereas CYP6N3 was rather consistently over-expressed across carbamate and DDT resistant populations. Other detoxification genes also up-regulated in permethrin resistant mosquitoes included a glucuronosyltransferase (AAEL014279-RA) and the glutathione-S transferases GSTS1 and GSTT3. Functional analyses further supported that CYP6P12 contributes to pyrethroid resistance in Ae. albopictus as transgenic expression of CYP6P12 in Drosophila was sufficient to confer pyrethroid resistance in these flies. Furthermore, molecular docking simulations predicted CYP6P12 possessing enzymatic activity towards pyrethroids. Patterns of polymorphism suggested early sign of selection acting on CYP6P12 but not on CYP6N3. The major role played by P450 in the absence of kdr mutations suggests that addition of the synergist PBO to pyrethroids could improve the efficacy of this insecticide class and overcome resistance in field populations of Ae. albopictus.

No MeSH data available.


Related in: MedlinePlus