TY - JOUR
T1 - Overcoming insecticide resistance through computational inhibitor design
AU - Correy, Galen J.
AU - Zaidman, Daniel
AU - Harmelin, Alon
AU - Mabbitt, Peter D.
AU - Calaora, Viviane
AU - James, Peter J.
AU - Kotze, Andrew C.
AU - Jackson, Colin J.
AU - London, Nir
N1 - Publisher Copyright: © 2019 National Academy of Sciences. All rights reserved.
PY - 2019/10/15
Y1 - 2019/10/15
N2 - 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 alpha E7 from the agricultural pest Lucilia cuprina as well as a common Gly137Asp alpha E7 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.
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 alpha E7 from the agricultural pest Lucilia cuprina as well as a common Gly137Asp alpha E7 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.
UR - http://www.scopus.com/inward/record.url?scp=85073315143&partnerID=8YFLogxK
U2 - https://doi.org/10.1073/pnas.1909130116
DO - https://doi.org/10.1073/pnas.1909130116
M3 - مقالة
SN - 0027-8424
VL - 116
SP - 21012
EP - 21021
JO - Proceedings of the National Academy of Sciences of the United States of America
JF - Proceedings of the National Academy of Sciences of the United States of America
IS - 42
ER -