Select small core structure carbamates exhibit high contact toxicity to "carbamate-resistant" strain malaria mosquitoes, Anopheles gambiae (Akron).
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...
Main Authors: | , , , , , , , , , , , , , , , |
---|---|
Format: | Article |
Language: | English |
Published: |
Public Library of Science (PLoS)
2012-01-01
|
Series: | PLoS ONE |
Online Access: | http://europepmc.org/articles/PMC3462181?pdf=render |
id |
doaj-5787d6ace9ba45baa6e7309d3a591b29 |
---|---|
record_format |
Article |
spelling |
doaj-5787d6ace9ba45baa6e7309d3a591b292020-11-25T01:55:54ZengPublic Library of Science (PLoS)PLoS ONE1932-62032012-01-01710e4671210.1371/journal.pone.0046712Select small core structure carbamates exhibit high contact toxicity to "carbamate-resistant" strain malaria mosquitoes, Anopheles gambiae (Akron).Dawn M WongJianyong LiQiao-Hong ChenQian HanJames M MutungaAnia WysinskiTroy D AndersonHaizhen DingTiffany L CarpenettiAstha VermaRafique IslamSally L PaulsonPolo C-H LamMaxim TotrovJeffrey R BloomquistPaul R CarlierAcetylcholinesterase (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.http://europepmc.org/articles/PMC3462181?pdf=render |
collection |
DOAJ |
language |
English |
format |
Article |
sources |
DOAJ |
author |
Dawn M Wong Jianyong Li Qiao-Hong Chen Qian Han James M Mutunga Ania Wysinski Troy D Anderson Haizhen Ding Tiffany L Carpenetti Astha Verma Rafique Islam Sally L Paulson Polo C-H Lam Maxim Totrov Jeffrey R Bloomquist Paul R Carlier |
spellingShingle |
Dawn M Wong Jianyong Li Qiao-Hong Chen Qian Han James M Mutunga Ania Wysinski Troy D Anderson Haizhen Ding Tiffany L Carpenetti Astha Verma Rafique Islam Sally L Paulson Polo C-H Lam Maxim Totrov Jeffrey R Bloomquist Paul R Carlier Select small core structure carbamates exhibit high contact toxicity to "carbamate-resistant" strain malaria mosquitoes, Anopheles gambiae (Akron). PLoS ONE |
author_facet |
Dawn M Wong Jianyong Li Qiao-Hong Chen Qian Han James M Mutunga Ania Wysinski Troy D Anderson Haizhen Ding Tiffany L Carpenetti Astha Verma Rafique Islam Sally L Paulson Polo C-H Lam Maxim Totrov Jeffrey R Bloomquist Paul R Carlier |
author_sort |
Dawn M Wong |
title |
Select small core structure carbamates exhibit high contact toxicity to "carbamate-resistant" strain malaria mosquitoes, Anopheles gambiae (Akron). |
title_short |
Select small core structure carbamates exhibit high contact toxicity to "carbamate-resistant" strain malaria mosquitoes, Anopheles gambiae (Akron). |
title_full |
Select small core structure carbamates exhibit high contact toxicity to "carbamate-resistant" strain malaria mosquitoes, Anopheles gambiae (Akron). |
title_fullStr |
Select small core structure carbamates exhibit high contact toxicity to "carbamate-resistant" strain malaria mosquitoes, Anopheles gambiae (Akron). |
title_full_unstemmed |
Select small core structure carbamates exhibit high contact toxicity to "carbamate-resistant" strain malaria mosquitoes, Anopheles gambiae (Akron). |
title_sort |
select small core structure carbamates exhibit high contact toxicity to "carbamate-resistant" strain malaria mosquitoes, anopheles gambiae (akron). |
publisher |
Public Library of Science (PLoS) |
series |
PLoS ONE |
issn |
1932-6203 |
publishDate |
2012-01-01 |
description |
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. |
url |
http://europepmc.org/articles/PMC3462181?pdf=render |
work_keys_str_mv |
AT dawnmwong selectsmallcorestructurecarbamatesexhibithighcontacttoxicitytocarbamateresistantstrainmalariamosquitoesanophelesgambiaeakron AT jianyongli selectsmallcorestructurecarbamatesexhibithighcontacttoxicitytocarbamateresistantstrainmalariamosquitoesanophelesgambiaeakron AT qiaohongchen selectsmallcorestructurecarbamatesexhibithighcontacttoxicitytocarbamateresistantstrainmalariamosquitoesanophelesgambiaeakron AT qianhan selectsmallcorestructurecarbamatesexhibithighcontacttoxicitytocarbamateresistantstrainmalariamosquitoesanophelesgambiaeakron AT jamesmmutunga selectsmallcorestructurecarbamatesexhibithighcontacttoxicitytocarbamateresistantstrainmalariamosquitoesanophelesgambiaeakron AT aniawysinski selectsmallcorestructurecarbamatesexhibithighcontacttoxicitytocarbamateresistantstrainmalariamosquitoesanophelesgambiaeakron AT troydanderson selectsmallcorestructurecarbamatesexhibithighcontacttoxicitytocarbamateresistantstrainmalariamosquitoesanophelesgambiaeakron AT haizhending selectsmallcorestructurecarbamatesexhibithighcontacttoxicitytocarbamateresistantstrainmalariamosquitoesanophelesgambiaeakron AT tiffanylcarpenetti selectsmallcorestructurecarbamatesexhibithighcontacttoxicitytocarbamateresistantstrainmalariamosquitoesanophelesgambiaeakron AT asthaverma selectsmallcorestructurecarbamatesexhibithighcontacttoxicitytocarbamateresistantstrainmalariamosquitoesanophelesgambiaeakron AT rafiqueislam selectsmallcorestructurecarbamatesexhibithighcontacttoxicitytocarbamateresistantstrainmalariamosquitoesanophelesgambiaeakron AT sallylpaulson selectsmallcorestructurecarbamatesexhibithighcontacttoxicitytocarbamateresistantstrainmalariamosquitoesanophelesgambiaeakron AT polochlam selectsmallcorestructurecarbamatesexhibithighcontacttoxicitytocarbamateresistantstrainmalariamosquitoesanophelesgambiaeakron AT maximtotrov selectsmallcorestructurecarbamatesexhibithighcontacttoxicitytocarbamateresistantstrainmalariamosquitoesanophelesgambiaeakron AT jeffreyrbloomquist selectsmallcorestructurecarbamatesexhibithighcontacttoxicitytocarbamateresistantstrainmalariamosquitoesanophelesgambiaeakron AT paulrcarlier selectsmallcorestructurecarbamatesexhibithighcontacttoxicitytocarbamateresistantstrainmalariamosquitoesanophelesgambiaeakron |
_version_ |
1724982652207890432 |