Developing novel drugs to target Leishmaniasis
Supervisor: Dr Shane Wilkinson
Project description
Estimates indicate that across tropical and sub-tropical regions of the World more than 12 million people suffer from various forms of Leishmaniasis, infections caused by protozoan parasites belonging to the genus Leishmania. With no prospect of a vaccine chemotherapy is of major importance. However, current treatments are unsatisfactory & the development of new drugs is a priority. Previous drug screening programmes carried out at SBCS have identified several, potent anti-parasitic nitro- & quinone-based compounds that show little/no cytotoxicity to mammalian cells. These compounds invariably function as prodrugs & following activation are postulated to mediate their mode of action by promoting DNA damage.
The aim of this PhD project is to build on these findings to:
- Establish whether these compounds promote DNA damage in parasite and mammalian cells
- Evaluate the role played by parasite DNA repair pathways to fix this damage
Additionally, the successful applicant will use tagged intracellular parasite lines for additional drug screening programmes. It is envisaged that by understanding how these bioreductive compounds mediate their anti-parasitic activities will inform the development of new chemical structures that have translational potential.
Facilities and training
The successful applicant will receive a comprehensive training in molecular biology & biochemical skills. Instructions in Good Microbiological practice will be given, with emphasis on the culturing & genetic manipulation of containment level 2 and 3 pathogens, as well as on mammalian tissue culture work.
Personalised training in writing and communication skills will be provided, complemented with generic transferable skills training from the QMUL Learning Institute.
References
- Unraveling the role of SNM1 in the DNA repair system of Trypanosoma brucei. Molecular Microbiology, Sullivan et al, 96 (2015) 827-838
- Evaluating aziridinyl nitrobenzamide compounds as leishmanicidal prodrugs. Antimicrobial Agents and Chemotherapy, Voak et al, 58 (2014), 370-377
- An essential Type I Nitroreductase from Leishmania major can be used to activate leishmanicidal prodrugs. Journal of Biological Chemistry, Voak et al, 288 (2013), 28466-28476.
- Evaluating 5-nitrofurans as trypanocidal agents, Antimicrobial Agents Chemotherapy, Bot et all, 57 (2013), 1638-1647.
- Trypanocidal activity of aziridinyl nitrobenzamide prodrug, Antimicrobial Agents and Chemotherapy, Bot et al, 54 (2010), 4246–4252.
- Exploiting the drug-activating properties of a novel trypanosomal nitroreductase, Antimicrobial Agents and Chemotherapy, Hall et al, 54 (2010), 1193–1199.
- A mechanism for cross-resistance to nifurtimox and benznidazole in trypanosome, Proceedings of the National Academy of Sciences USA,105 (2008), 5022-5027.