New generation insecticides: investigating mosquito metabolism for early identification of resistance genes.

Insecticide resistance is the major threat to most insect borne diseases in the developing world, particularly mosquitoes that transmit malaria, dengue fever and zika.  New insecticides are being released in Africa to tackle malaria. This project will investigate how these insecticides are metabolised in order to design new generation early warning systems to pre-empt resistance. 

Where does this project lie in the translational pathway?

T1; this  project is fundamental to understanding how insects are protected against chemical insult.   

What are the methodological aspects of the PhD project?

Enzyme kinetics; in silico/ computational modelling; recombinant DNA and protein methods; proteomics; metabolomics; analytical chemistry (e.g. HPLC, LC and GC MS/MS;);  transgenics;  microscopy; immunohistochemistry; Industry QC (ISO/GLP).       

What are the expected outputs of the PhD project?

1, Publications in specialist (biochemical, insect) and general journals e.g. JBC, Biochem J, PNAS, Curr Biol,  IBMB,

2. Pilot data for funding applications  e.g. BBSRC and Wellcome Trust

3. Development of new IP, tools and paradigms to counteract insecticide resistance 

External industry links or training opportunities available for the student.

IVCC, a non-academic Product Development Partnership of major Agrochemicals and related companies,  will provide financial and training support in developing target product profiles and development of product development skills.   
Cypex Ltd, Dundee, a SME,  will host the student on secondment to  provide specialist training in scale-up protein production and insect cell work.  They will also provide high value training in biotech industry QC manufacturing process, in particualar Good Lab Practice (GLP)   and ISO.    

Required skills/experience/aptitudes

Degree in biological or chemical discipline.

Key publications that relate to this proposed project.

Yunta, C., Grisales, N., Nász, S., Hemmings, K., Pignatelli, P., Voice, M., Ranson, H., Paine, M.J.I., (2016) Pyriproxyfen is metabolized by P450s associated with pyrethroid resistance in An. gambiae. Insect Biochem. Mol. Biol. 78, 50–57. doi:10.1016/j.ibmb.2016.09.001

Ismail, H., O’Neill, P., Hong, D.,  Finn, R.D., Henderson, C.J. Wright, A. T., Cravatt, B. F., Hemingway, J., and Paine, M. J. I. (2013) Pyrethroid Activity-Based Probes for Profiling Cytochrome P450 Activities Associated with Insecticide Interactions Proc National Acad Sci. USA. Nov 18th early edition. doi 10.1073/pnas.1320185110

Edi, C. V., Djogbenou, L., Jenkins, A. M., Regna, K., Muskavitch, M. A., Poupardin, R., Jones, C. M., Essandoh, J., Ketoh, G. K., Paine, M. J., Koudou, B. G., Donnelly, M. J., Ranson, H., and Weetman, D. (2014) CYP6 P450 Enzymes and ACE-1 Duplication Produce Extreme and Multiple Insecticide Resistance in the Malaria Mosquito Anopheles gambiae. PLoS genetics 10, e1004236

Bradley J. Stevenson , Jaclyn Bibby , Patricia Pignatelli , Sant Muangnoicharoen , Paul M. O’Neill , Lu-Yun Lian , Pie Müller, Dimitra Nikou , Andrew Steven , Janet Hemingway , Michael J. Sutcliffe , Mark J. I. Paine  (2011) Cytochrome P450 6M2 from the malaria vector Anopheles gambiae metabolizes pyrethroids: sequential metabolism of deltamethrin revealed.  Insect Biochem Mol Biol.  41 492 – 50

David J.P, Ismail H.M, Chandor-Proust A, Paine M.J.I (2013) Role of cytochrome P450s in insecticide resistance: impact on the control of mosquito-borne diseases and use of insecticides on Earth. Philos Trans R Soc Lond B Biol Sci 368: 20120429. (Top 10 most cited in 2013)