Select Small Core Structure Carbamates Exhibit High Contact Toxicity to 'Carbamate-Resistant' Strain Malaria Mosquitoes, Anopheles gambiae (Akron)
| Autor: | James M. Mutunga, Jeffrey R. Bloomquist, Qian Han, Qiao-Hong Chen, Jianyong Li, Astha Verma, Ania Wysinski, Tiffany L. Carpenetti, Paul R. Carlier, Haizhen Ding, Troy D. Anderson, Sally L. Paulson, Maxim Totrov, Dawn M. Wong, Polo Chun Hung Lam, Rafique Islam |
|---|---|
| Rok vydání: | 2012 |
| Předmět: |
Insecticides
Aldicarb medicine.medical_treatment Anopheles gambiae Drug Resistance lcsh:Medicine Biochemistry Mosquitoes Polymerase Chain Reaction chemistry.chemical_compound Drug Discovery Cholinesterases lcsh:Science chemistry.chemical_classification 0303 health sciences Multidisciplinary Molecular Structure biology Strain (chemistry) 030302 biochemistry & molecular biology Agriculture Neurochemistry Oxime Acetylcholinesterase 3. Good health Chemistry Infectious Diseases Toxicity Medicine Electrophoresis Polyacrylamide Gel Neurochemicals Polymorphism Restriction Fragment Length Research Article Drugs and Devices Carbamate Drug Research and Development Mutation Missense Microbiology Vector Biology 03 medical and health sciences Anopheles parasitic diseases Parasitic Diseases medicine Animals Pesticides Biology 030304 developmental biology lcsh:R Tropical Diseases (Non-Neglected) Vectors and Hosts biology.organism_classification Molecular biology Acetylcholine Malaria Insect Vectors Enzyme chemistry lcsh:Q Pest Control Carbamates Cholinesterase Inhibitors Medicinal Chemistry Zoology Entomology Neuroscience |
| Zdroj: | PLoS ONE, Vol 7, Iss 10, p e46712 (2012) PLoS ONE |
| ISSN: | 1932-6203 |
| DOI: | 10.1371/journal.pone.0046712 |
| Popis: | 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 (LC(50)>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 (LC(50) = 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. |
| Databáze: | OpenAIRE |
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