Select Small Core Structure Carbamates Exhibit High Contact Toxicity to “Carbamate-Resistant” Strain Malaria Mosquitoes, Anopheles gambiae (Akron)

PLoS One

Jianyong Li¹  Qian Han¹  Haizhen Ding¹  Qiao-Hong Chen²  Dawn M. Wong²  Astha Verma²  Paul R. Carlier³  Rafique Islam³  James M. Mutunga⁴  Tiffany L. Carpenetti⁴  Troy D. Anderson⁴  Ania Wysinski⁴  Sally L. Paulson⁴  Jeffrey R. Bloomquist⁴  Polo C.-H. Lam⁵  Maxim Totrov⁵ 

[1] Department of Biochemistry, Virginia Tech, Blacksburg, Virginia, United States of America;Department of Chemistry, Virginia Tech, Blacksburg, Virginia, United States of America;Department of Entomology and Nematology, Emerging Pathogens Institute, University of Florida, Gainesville, Florida, United States of America;Department of Entomology, Virginia Tech, Blacksburg, Virginia, United States of America;Molsoft LLC, San Diego, California, United States of America

关键词: Carbamates;    Mosquitoes;    Toxicity;    Insecticides;    Anopheles gambiae;    Enzyme inhibitors;    Oximes;    Recombinant proteins;   

DOI  :  10.1371/journal.pone.0046712

学科分类：医学（综合）

来源: Public Library of Science

【 摘 要 】

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 (kcat) 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.

【 授权许可】

CC BY