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Overcoming insecticide resistance through computational inhibitor design

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

Description

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...[Show more]

dc.contributor.authorCorrey, Galen
dc.contributor.authorZaidman, Daniel
dc.contributor.authorHarmelin, Alon
dc.contributor.authorCarvalho, Silvia
dc.contributor.authorMabbitt, Peter
dc.contributor.authorCalaora, Viviane
dc.contributor.authorJames, Peter J.
dc.contributor.authorKotze, Andrew
dc.contributor.authorJackson, Colin
dc.contributor.authorLondon, Nir
dc.date.accessioned2020-07-08T03:23:56Z
dc.identifier.issn0027-8424
dc.identifier.urihttp://hdl.handle.net/1885/205932
dc.description.abstractInsecticides 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 potentiating 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
dc.description.sponsorshipThis research was supported by an Australian Postgraduate Award (to G.J.C.), Australian Science and Industry Endowment Fund PF14-099 (to P.D.M. and C.J.J.), Australian Research Council Future Fellowship FT140101059 (to C.J.J.), Israel Science Foundation Grant 1097/16 (to N.L.), and German–Israeli Foundation Grant I-2483-302.5/2017 (to N.L.). Additionally, N.L. is the incumbent of the Alan and Laraine Fischer Career Development Chair.
dc.format.mimetypeapplication/pdf
dc.language.isoen_AU
dc.publisherNational Academy of Sciences (USA)
dc.rights© 2019 The Author(s)
dc.sourcePNAS - Proceedings of the National Academy of Sciences of the United States of America
dc.subjectcovalent docking
dc.subjectinsecticide resistance
dc.subjectorganophosphates
dc.subjectcarboxylesterase
dc.subjectLucilia cuprina
dc.titleOvercoming insecticide resistance through computational inhibitor design
dc.typeJournal article
local.description.notesImported from ARIES
local.identifier.citationvolume116
dcterms.dateAccepted2019-09-12
dc.date.issued2019-10-01
local.identifier.absfor030403 - Characterisation of Biological Macromolecules
local.identifier.ariespublicationu5786633xPUB1114
local.publisher.urlhttps://www.pnas.org/
local.type.statusPublished Version
local.contributor.affiliationCorrey, Galen, College of Science, ANU
local.contributor.affiliationZaidman, Daniel, The Weizmann Institute of Science
local.contributor.affiliationHarmelin, Alon, The Weizmann Institute of Science
local.contributor.affiliationCarvalho, Silvia, The Weizmann Institute of Science
local.contributor.affiliationMabbitt, Peter, College of Science, ANU
local.contributor.affiliationCalaora, Viviane, BioTransfer
local.contributor.affiliationJames, Peter J., The University of Queensland
local.contributor.affiliationKotze, Andrew, CSIRO Livestock
local.contributor.affiliationJackson, Colin, College of Science, ANU
local.contributor.affiliationLondon, Nir, The Weizmann Institute of Science
local.description.embargo2037-12-31
dc.relationhttp://purl.org/au-research/grants/arc/FT140101059
local.bibliographicCitation.issue42
local.bibliographicCitation.startpage21012
local.bibliographicCitation.lastpage21021
local.identifier.doi10.1073/pnas.1909130116
local.identifier.absseo970103 - Expanding Knowledge in the Chemical Sciences
dc.date.updated2020-06-23T00:56:40Z
local.identifier.scopusID2-s2.0-85073315143
dcterms.accessRightsOpen Access via publisher site
CollectionsANU Research Publications

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