Abstract
Acetylcholinesterase (AChE) is a proven target for control of the malaria mosquito (Anopheles gambiae). Unfortunately, a single amino acid mutation (G119S) in An. gambiae AChE-1 (AgAChE) confers resistance to the AChE inhibitors currently approved by the World Health Organization for indoor residual spraying. In this report, we describe several carbamate inhibitors that potently inhibit G119S AgAChE and that are contact-toxic to carbamate-resistant An. gambiae. PCR-RFLP analysis was used to confirm that carbamate-susceptible G3 and carbamate-resistant Akron strains of An. gambiae carry wild-type (WT) and G119S AChE, respectively. G119S AgAChE was expressed and purified for the first time, and was shown to have only 3% of the turnover number (k cat) of the WT enzyme. Twelve carbamates were then assayed for inhibition of these enzymes. High resistance ratios (>2,500-fold) were observed for carbamates bearing a benzene ring core, consistent with the carbamate-resistant phenotype of the G119S enzyme. Interestingly, resistance ratios for two oxime methylcarbamates, and for five pyrazol-4-yl methylcarbamates were found to be much lower (4- to 65-fold). The toxicities of these carbamates to live G3 and Akron strain An. gambiae were determined. As expected from the enzyme resistance ratios, carbamates bearing a benzene ring core showed low toxicity to Akron strain An. gambiae (LC50>5,000 μg/mL). However, one oxime methylcarbamate (aldicarb) and five pyrazol-4-yl methylcarbamates (4a–e) showed good to excellent toxicity to the Akron strain (LC50 = 32–650 μg/mL). These results suggest that appropriately functionalized “small-core” carbamates could function as a resistance-breaking anticholinesterase insecticides against the malaria mosquito.
Highlights
Malaria presents an enormous burden in sub-Saharan Africa, killing nearly 700,000 people each year and sickening hundreds of millions more [1,2,3]
The World Health Organization Pesticide Evaluation Scheme (WHOPES, http://www.who.int/ whopes/en/) has approved five insecticidal AChE inhibitors for indoor residual spraying (IRS), but none have been approved for use on insecticide treated nets (ITNs)
This study showed that the G122A mutant of recombinant hAChE (rhAChE), which corresponds to G119A in An. gambiae AChE-1 (AgAChE), suffered a 18-fold reduction in kcat relative to WT rhAChE
Summary
Malaria presents an enormous burden in sub-Saharan Africa, killing nearly 700,000 people each year and sickening hundreds of millions more [1,2,3]. Control of the diseasetransmitting mosquito, Anopheles gambiae is a proven strategy to reduce malaria transmission [2,4]. Only two biological targets have been used to control adult mosquitoes [5]: acetylcholinesterase (AChE, EC 3.1.1.7) and the voltage-gated sodium ion channel [6,7,8]. The World Health Organization Pesticide Evaluation Scheme (WHOPES, http://www.who.int/ whopes/en/) has approved five insecticidal AChE inhibitors for indoor residual spraying (IRS), but none have been approved for use on insecticide treated nets (ITNs). ITNs are impregnated with pyrethroid modulators of the voltage-gated sodium ion channel. Emerging pyrethroid-resistant strains of An. gambiae put this malaria control strategy at risk [9,10]
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