Novel AChE Inhibitors for Sustainable Insecticide Resistance Management

Abstract

Resistance to insecticides has become a critical issue in pest management and it is particularly chronic in the control of human disease vectors. The gravity of this situation is being exacerbated since there has not been a new insecticide class produced for over twenty years. Reasoned strategies have been developed to limit resistance spread but have proven difficult to implement in the field. Here we propose a new conceptual strategy based on inhibitors that preferentially target mosquitoes already resistant to a currently used insecticide. Application of such inhibitors in rotation with the insecticide against which resistance has been selected initially is expected to restore vector control efficacy and reduce the odds of neo-resistance. We validated this strategy by screening for inhibitors of the G119S mutated acetylcholinesterase-1 (AChE1), which mediates insensitivity to the widely used organophosphates (OP) and carbamates (CX) insecticides. PyrimidineTrione Furan-substituted (PTF) compounds came out as best hits, acting biochemically as reversible and competitive inhibitors of mosquito AChE1 and preferentially inhibiting the mutated form, insensitive to OP and CX. PTF application in bioassays preferentially killed OP-resistant Culex pipiens and Anopheles gambiae larvae as a consequence of AChE1 inhibition. Modeling the evolution of frequencies of wild type and OP-insensitive AChE1 alleles in PTF-treated populations using the selectivity parameters estimated from bioassays predicts a rapid rise in the wild type allele frequency. This study identifies the first compound class that preferentially targets OP-resistant mosquitoes, thus restoring OP-susceptibility, which validates a new prospect of sustainable insecticide resistance management.

Acetylcholinesterases from the Disease Vectors Aedes aegypti and Anopheles gambiae: Functional Characterization and Comparisons with Vertebrate Orthologues

“…Likewise, recent work targeting the catalytic serine residue with covalent inhibitors containing a carbamate functionality has shown that considerable selectivity ratios can be achieved for mosquito over vertebrate enzymes [ 31 , 32 , 54 , 61 ]. While the potential of covalent inhibitors has been investigated in a number of studies, inhibitors with a different mode of action, such as non-covalent inhibitors, are less well explored [ 62 ]. Another major concern in insecticide development is to overcome the increasing resistance to AChE inhibitors conferred by e .…”

“…the G119S mutation. Novel small-core carbamates have been designed [ 54 ], and it has also been shown that it is possible to target resistant mutant enzymes with non-covalent inhibitors [ 62 ].…”

Synthesis, Larvicidal and Acetylcholinesterase Inhibitory Activities of Carvacrol/Thymol and Derivatives

“…15 The inhibition of acetylcholinesterase is the major mode of action for most insecticides especially organophosphates and carbamates, and this effect may be responsible for larvicidal activity on against Culex quinquefasciatus, Culex pipiens, Anopheles gambiae and Aedes aegypti. 16,17 In this context, the aims of this study was to obtain derivatives of carvacrol/thymol and to investigate the inhibitory activity of acetylcholinesterase and larvicidal against Aedes aegypti larvae. The synthesis of the compounds was carried out according to the procedure shown in Figures 1 and 2.…”

Discovery of Species-selective and Resistance-breaking Anticholinesterase Insecticides for the Malaria Mosquito

“…Downsampling and purchase of additional analogs led to the identification of seven barbaturic acid-furan or –thiophene analogs that inhibited G119S Cp AChE ≥10-fold more strongly than WT Cp AChE (e.g. 28 ) [68]. …”