Molecular, Biochemical, and Toxicological Evaluation of Anticholinesterases for control of the Malaria Mosquito, Anopheles gambiae

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dc.contributor.authorMutunga, James Mutukuen
dc.contributor.committeechairBloomquist, Jeffrey R.en
dc.contributor.committeecochairMyles, Kevin M.en
dc.contributor.committeememberAnderson, Troy D.en
dc.contributor.committeememberPaulson, Sally L.en
dc.contributor.committeememberSharakhov, Igor V.en
dc.contributor.departmentEntomologyen
dc.date.accessioned2015-01-23T19:28:02Zen
dc.date.adate2011-05-26en
dc.date.available2015-01-23T19:28:02Zen
dc.date.issued2011-04-28en
dc.date.rdate2015-01-18en
dc.date.sdate2011-05-12en
dc.description.abstractPyrethroids are the only class of insecticides approved by the World Health Organization (WHO) for use in insecticide treated nets (ITNs), the first line of malaria vector control. Widespread resistance development to pyrethroids undermines current control efforts, and hence an urgent need for alternative chemistries. I report the evaluation of pharmacological differences between insect and vertebrate acetylcholinesterase (AChE) as well as selectivity and toxicity testing of new carbamate insecticides on Anopheles gambiae, the African malaria mosquito. AChE gorge pharmacology data revealed differences between insect and vertebrate AChE that can be exploited in the design of a bivalent insecticide. Toxicokinetic analysis showed that metabolic detoxication and cuticular penetration affect toxicity of carbamates in a manner dependent on the chemical structure. Structure activity relationships of side-chain branched N-methylcarbamates emphasized the importance of structural complementarity of ligands to the AChE catalytic active site and the substrate, acetylcholine. Monovalent pyrazoles and acetophenone oxime carbamates were toxic to both susceptible and carbamate-resistant mosquitoes carrying a G119S mutation within the catalytic site. A bivalent phthalimide-pyrazole carbamate and sulfenylated phenyl N-methyl carbamates were highly toxic when topically applied onto insect but less toxic by treated filter paper assays. In vitro evaluation of a molecular mosquito-selectivity model using AChE peripheral site ligands confirmed that selectivity of PRC 472 was due to presence of I70 in mosquito, which is Y70 in human AChE. The findings presented here are important steps in the on-going search of a mosquito-selective and resistance mitigating carbamate insecticide for control of malaria mosquitoes.en
dc.description.degreePh. D.en
dc.format.mediumETDen
dc.identifier.otheretd-05122011-181858en
dc.identifier.sourceurlhttp://scholar.lib.vt.edu/theses/available/etd-05122011-181858/en
dc.identifier.urihttp://hdl.handle.net/10919/51210en
dc.language.isoen_USen
dc.publisherVirginia Techen
dc.relation.haspartMutunga_JM_D_2011.pdfen
dc.rightsIn Copyrighten
dc.rights.urihttp://rightsstatements.org/vocab/InC/1.0/en
dc.subjectN-methylcarbamatesen
dc.subjectakron strainen
dc.subjecttacrine dimersen
dc.subjectacetylcholinesteraseen
dc.subjectpyrazolesen
dc.subjectoximesen
dc.subjectactive site gorgeen
dc.subjectbivalent carbamatesen
dc.titleMolecular, Biochemical, and Toxicological Evaluation of Anticholinesterases for control of the Malaria Mosquito, Anopheles gambiaeen
dc.typeDissertationen
thesis.degree.disciplineEntomologyen
thesis.degree.grantorVirginia Polytechnic Institute and State Universityen
thesis.degree.leveldoctoralen
thesis.degree.namePh. D.en

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