Drug Discovery in Parasite Lipid Metabolism

Tropical infectious diseases affect ca. 50% of the global population, a significant proportion of these are caused by protozoan parasites, killing millions of people a year, predominately in the poorest countries in Africa.

These include well known big killers such as malaria, caused by the mosquito transmitted parasite Plasmodium falciparum, to one of the most neglected diseases on the planet, African sleeping sickness, and the related disease in cattle, Nagana, are caused by the Tsetse fly transmitted parasite Trypanosoma brucei. The WHO estimates that Human African Trypanosomiasis constitutes a serious health risk to 60 million people in sub-Saharan Africa, with an estimated 50,000 fatalities. These disease cause serious social and economic problems in Africa, yet current drug therapies which are several decades old at best, are woefully inadequate, due to toxicity, hard to administer, expensive, and the incidence of treatment failure is increasing, possibly due to resistance. Consequently, there is an urgent need for the development of novel treatments.

The Smith group is working on various protozoan parasites, focusing on their unusual lipid metabolism. Initially we use T.brucei, just for easy of obtaining large amounts of material, but later Plasmodium, T.cruzi and Leishmania spp as well.
Surprisingly little is known about the lipid biosynthetic processes in most protozoan parasites and detailed structural and mechanistic studies will reveal novel therapeutic targets.

The multi-disciplinary research approach involves:
(a) In vivo and in vitro biosynthetic studies, to investigate how the parasites de novo synthesise their lipids.
(b) Bioinformatics, molecular biology and molecular parasitology are used to clone novel genes, allowing gene-knockout and/or RNAi approaches to genetically validate them as drug targets.
(c) Biochemical phenotyping of these modified parasites using labelling methods, quantification of metabolites and proteins, enzymatic assays, various mass spectrometer methods and lipidomic approaches to help us understand the parasite’s responses.
(d) Recombinant expression and development of enzymatic assays, ultimately for high-throughput screening, in conjunction with the design and chemical synthesis of biosynthetic inhibitors as drug leads.
The Smith laboratory and is well-funded and well-equipped, including a cat 3 suite to culture the parasites, and has easy on site access to several suitable mass spectrometers to conduct proteomic studies. The expertise in the laboratory will provide an excellent basis for such a study and will offer a PhD student a fantastic opportunity for extensive training in a wide variety of techniques including: molecular parasitology, biochemistry, mass spectrometry, including proteomics, and bioinformatics, but to mention a few.

The ultimate goal of our research is to form new, easy to make, affordable, easy to administer, drugs in the fight against these and related protozoan transmitted Third world diseases that affect Africa and the sub-tropics.