RT Journal Article
SR Electronic
T1 Overcoming insecticide resistance through computational inhibitor design
JF bioRxiv
FD Cold Spring Harbor Laboratory
SP 161430
DO 10.1101/161430
A1 Galen J. Correy
A1 Daniel Zaidman
A1 Silvia Carvalho
A1 Peter D. Mabbitt
A1 Peter J. James
A1 Andrew C. Kotze
A1 Nir London
A1 Colin J. Jackson
YR 2017
UL http://biorxiv.org/content/early/2017/07/10/161430.abstract
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 computational design to produce nano/pico-molar 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 no intrinsic apparent toxicity, 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. These compounds represent a solution to insecticide resistance as well as to environmental concerns regarding OPs, allowing significant reduction of use without compromising efficacy.