Overcoming insecticide resistance through computational inhibitor design

Galen J. Correy; Daniel Zaidman; Alon Harmelin; Silvia Carvalho; Peter D. Mabbitt; Viviane Calaora; Peter J. James; Andrew C. Kotze; Colin J. Jackson; Nir London

doi:10.1073/pnas.1909130116

Overcoming insecticide resistance through computational inhibitor design

Galen J. Correy, Daniel Zaidman, Alon Harmelin, Silvia Carvalho, Peter D. Mabbitt, Viviane Calaora, Peter J. James, Andrew C. Kotze, Colin J. Jackson^*, Nir London

^*Corresponding author for this work

Research output: Contribution to journal › Article › peer-review

31 Citations (Scopus)

Abstract

Insecticides allow control of agricultural pests and disease vectors and are vital for global food security and health. The evolution of resistance to insecticides, such as organophosphates (OPs), is a serious and growing concern. OP resistance often involves sequestration or hydrolysis of OPs by carboxylesterases. Inhibiting carboxylesterases could, therefore, restore the effectiveness of OPs for which resistance has evolved. Here, we use covalent virtual screening to produce nano-/picomolar boronic acid inhibitors of the carboxylesterase αE7 from the agricultural pest Lucilia cuprina as well as a common Gly137Asp αE7 mutant that confers OP resistance. These inhibitors, with high selectivity against human acetylcholinesterase and low to no toxicity in human cells and in mice, act synergistically with the OPs diazinon and malathion to reduce the amount of OP required to kill L. cuprina by up to 16-fold and abolish resistance. The compounds exhibit broad utility in significantly po-tentiating another OP, chlorpyrifos, against the common pest, the peach–potato aphid (Myzus persicae). These compounds represent a solution to OP resistance as well as to environmental concerns regarding overuse of OPs, allowing significant reduction of use without compromising efficacy.

Original language	English
Pages (from-to)	21012-21021
Number of pages	10
Journal	Proceedings of the National Academy of Sciences of the United States of America
Volume	116
Issue number	42
DOIs	https://doi.org/10.1073/pnas.1909130116
Publication status	Published - 15 Oct 2019

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title = "Overcoming insecticide resistance through computational inhibitor design",

abstract = "Insecticides allow control of agricultural pests and disease vectors and are vital for global food security and health. The evolution of resistance to insecticides, such as organophosphates (OPs), is a serious and growing concern. OP resistance often involves sequestration or hydrolysis of OPs by carboxylesterases. Inhibiting carboxylesterases could, therefore, restore the effectiveness of OPs for which resistance has evolved. Here, we use covalent virtual screening to produce nano-/picomolar boronic acid inhibitors of the carboxylesterase αE7 from the agricultural pest Lucilia cuprina as well as a common Gly137Asp αE7 mutant that confers OP resistance. These inhibitors, with high selectivity against human acetylcholinesterase and low to no toxicity in human cells and in mice, act synergistically with the OPs diazinon and malathion to reduce the amount of OP required to kill L. cuprina by up to 16-fold and abolish resistance. The compounds exhibit broad utility in significantly po-tentiating another OP, chlorpyrifos, against the common pest, the peach–potato aphid (Myzus persicae). These compounds represent a solution to OP resistance as well as to environmental concerns regarding overuse of OPs, allowing significant reduction of use without compromising efficacy.",

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AU - Zaidman, Daniel

AU - Harmelin, Alon

AU - Carvalho, Silvia

AU - Mabbitt, Peter D.

AU - Calaora, Viviane

AU - James, Peter J.

AU - Kotze, Andrew C.

AU - Jackson, Colin J.

AU - London, Nir

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AB - Insecticides allow control of agricultural pests and disease vectors and are vital for global food security and health. The evolution of resistance to insecticides, such as organophosphates (OPs), is a serious and growing concern. OP resistance often involves sequestration or hydrolysis of OPs by carboxylesterases. Inhibiting carboxylesterases could, therefore, restore the effectiveness of OPs for which resistance has evolved. Here, we use covalent virtual screening to produce nano-/picomolar boronic acid inhibitors of the carboxylesterase αE7 from the agricultural pest Lucilia cuprina as well as a common Gly137Asp αE7 mutant that confers OP resistance. These inhibitors, with high selectivity against human acetylcholinesterase and low to no toxicity in human cells and in mice, act synergistically with the OPs diazinon and malathion to reduce the amount of OP required to kill L. cuprina by up to 16-fold and abolish resistance. The compounds exhibit broad utility in significantly po-tentiating another OP, chlorpyrifos, against the common pest, the peach–potato aphid (Myzus persicae). These compounds represent a solution to OP resistance as well as to environmental concerns regarding overuse of OPs, allowing significant reduction of use without compromising efficacy.

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Overcoming insecticide resistance through computational inhibitor design

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