Lees, Rosemary S.;
Ismail, Hanafy M.;
Logan, Rhiannon A. E.;
Malone, David;
Davies, Rachel;
Anthousi, Amalia;
Adolfi, Adriana;
Lycett, Gareth J.;
Paine, Mark J. I.
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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Media type:
E-Article
Title:
New insecticide screening platforms indicate that Mitochondrial Complex I inhibitors are susceptible to cross-resistance by mosquito P450s that metabolise pyrethroids
Contributor:
Lees, Rosemary S.;
Ismail, Hanafy M.;
Logan, Rhiannon A. E.;
Malone, David;
Davies, Rachel;
Anthousi, Amalia;
Adolfi, Adriana;
Lycett, Gareth J.;
Paine, Mark J. I.
Published:
Springer Science and Business Media LLC, 2020
Published in:
Scientific Reports, 10 (2020) 1
Language:
English
DOI:
10.1038/s41598-020-73267-x
ISSN:
2045-2322
Origination:
Footnote:
Description:
<jats:title>Abstract</jats:title><jats:p>Fenazaquin, pyridaben, tolfenpyrad and fenpyroximate are Complex I inhibitors offering a new mode of action for insecticidal malaria vector control<jats:italic>.</jats:italic> 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 <jats:italic>Anopheles gambiae</jats:italic> (CYPs 6M2, 6P3, 6P4, 6P5, 9J5, 9K1, 6Z2) and <jats:italic>An. funestus</jats:italic> (CYP6P9a). All compounds were highly susceptible. Transgenic <jats:italic>An. gambiae</jats:italic> overexpressing CYP6M2 or CYP6P3 showed reduced mortality when exposed to fenpyroximate and tolfenpyrad. Mortality from fenpyroximate was also reduced in pyrethroid-resistant strains of <jats:italic>An. gambiae</jats:italic> (VK7 2014 and Tiassalé 13) and <jats:italic>An. funestus</jats:italic> (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.</jats:p>