Professor Alan Fairlamb CBE, FLS, FRSE, FMedSci, FSB
Biochemical Drug Targets in Parasites
Better, safer and affordable drugs are needed for neglected tropical parasitic diseases. My research interests cover the early aspects of the drug discovery process, including discovery of novel drug targets, their mechanistic and structural characterisation and their validation using genetic and chemical approaches. My studies on the modes of drug action and the mechanisms by which parasites acquire resistance to drugs such as the arsenical, melarsoprol, resulted in the discovery of trypanothione, a metabolite unique to trypanosomatid parasites responsible for human African trypanosomiasis, Chagas' disease and leishmaniasis. Trypanothione and its ancillary enzymes are attractive drug targets, because they play a central role in thiol-redox homeostasis, in defence against chemical and oxidative stress, in resistance to antimonial drugs and in the metabolism of deoxyribonucleotides and methylglyoxal. In particular, the unique biosynthetic enzyme, trypanothione synthetase, has been shown to be an essential and druggable target. My research team has also established that certain enzymes of folate, pterin and pyridoxal metabolism are attractive drug targets in trypanosomes. Currently we are investigating the modes of action of potential new therapies for trypanosomiasis and leishmaniasis, including fexinidazole and PA-824.
1. H. B. Ong, W. S. Lee, S. Patterson, S. Wyllie, A. H. Fairlamb, Homoserine and quorum-sensing acyl homoserine lactones as alternative sources of threonine: a potential role for homoserine kinase in insect-stage Trypanosoma brucei, Mol. Microbiol. 95, 143-156 (2015).
2. M. R. Perry, V. K. Prajapati, J. Menten, A. Raab, J. Feldmann, D. Chakraborti, S. Sundar, A. H. Fairlamb, M. Boelaert, A. Picado, Arsenic exposure and outcomes of antimonial treatment in visceral leishmaniasis patients in Bihar, India: a retrospective cohort study, PLoS Negl. Trop. Dis. 9, e0003518 (2015).
3. L. Hobley, S. H. Kim, Y. Maezato, S. Wyllie, A. H. Fairlamb, N. R. Stanley-Wall, A. J. Michael, Norspermidine is not a self-produced trigger for biofilm disassembly, Cell 156, 844-854 (2014).
4. A. J. Roberts, L. S. Torrie, S. Wyllie, A. H. Fairlamb, Biochemical and genetic characterisation of Trypanosoma cruzi N-myristoyltransferase, Biochem. J. 459, 323-332 (2014).
5. S. Nguyen, D. C. Jones, S. Wyllie, A. H. Fairlamb, M. A. Phillips, Allosteric activation of trypanosomatid deoxyhypusine synthase by a catalytically dead paralog, J. Biol. Chem. 288, 15256-15267 (2013).
6. H. B. Ong, N. Sienkiewicz, S. Wyllie, S. Patterson, A. H. Fairlamb, Trypanosoma brucei (UMP synthase null mutants) are avirulent in mice, but recover virulence upon prolonged culture in vitro while retaining pyrimidine auxotrophy, Mol. Microbiol. 90, 443-455 (2013).
7. S. Patterson, S. Wyllie, L. Stojanovski, M. R. Perry, F. R. Simeons, S. Norval, M. Osuna-Cabello, R. M. De, K. D. Read, A. H. Fairlamb, The R enantiomer of the anti-tubercular drug PA-824 as a potential oral treatment for visceral leishmaniasis, Antimicrob. Agents Chemother. 57, 4699-4706 (2013).
8. M. R. Perry, S. Wyllie, A. Raab, J. Feldmann, A. H. Fairlamb, Chronic exposure to arsenic in drinking water can lead to resistance to antimonial drugs in a mouse model of visceral leishmaniasis, Proc. Natl. Acad. Sci. USA 110, 19932-19937 (2013).
9. S. Wyllie, S. Patterson, A. H. Fairlamb, Assessing the essentiality of Leishmania donovani nitroreductase and its role in nitro drug activation, Antimicrob. Agents Chemother. 57, 901-906 (2013).
10. M. De Rycker, S. O'Neill, D. Joshi, L. Campbell, D. W. Gray, A. H. Fairlamb, A static-cidal assay for Trypanosoma brucei to aid hit prioritisation for progression into drug discovery programmes, PLoS Negl. Trop. Dis. 6, e1932 (2012).
11. A. H. Fairlamb, Infectious disease: Genomics decodes drug action, Nature 482, 167-169 (2012).
12. D. C. Jones, M. S. Alphey, S. Wyllie, A. H. Fairlamb, Chemical, genetic and structural assessment of pyridoxal kinase as a drug target in the African trypanosome, Mol. Microbiol. 86, 51-64 (2012).
13. S. Wyllie, S. Patterson, L. Stojanovski, F. R. Simeons, S. Norval, R. Kime, K. D. Read, A. H. Fairlamb, The anti-trypanosome drug fexinidazole shows potential for treating visceral leishmaniasis, Sci. Transl. Med 4, 119re1 (2012).
14. J. Konig, S. Wyllie, G. Wells, M. F. Stevens, P. G. Wyatt, A. H. Fairlamb, Antitumor quinol PMX464 is a cytocidal anti-trypanosomal inhibitor targeting trypanothione metabolism, J. Biol. Chem. 286, 8523-8533 (2011).
15. H. B. Ong, N. Sienkiewicz, S. Wyllie, A. H. Fairlamb, Dissecting the metabolic roles of pteridine reductase 1 in Trypanosoma brucei and Leishmania major, J. Biol. Chem. 286, 10429-10438 (2011).
16. S. Patterson, M. S. Alphey, D. C. Jones, E. J. Shanks, I. P. Street, J. A. Frearson, P. G. Wyatt, I. H. Gilbert, A. H. Fairlamb, Dihydroquinazolines as a novel class of Trypanosoma brucei trypanothione reductase inhibitors: discovery, synthesis, and characterization of their binding mode by protein crystallography, J. Med. Chem. 54, 6514-6530 (2011).
17. P. G. Wyatt, I. H. Gilbert, K. D. Read, A. H. Fairlamb, Target validation: linking target and chemical properties to desired product profile, Curr. Top. Med. Chem. 11, 1275-1283 (2011).
18. J. A. Frearson, S. Brand, S. P. McElroy, L. A. T. Cleghorn, O. Smid, L. Stojanovski, H. P. Price, M. L. S. Guther, L. S. Torrie, D. A. Robinson, I. Hallyburton, C. P. Mpamhanga, J. A. Brannigan, A. J. Wilkinson, M. Hodgkinson, R. Hui, W. Qiu, O. G. Raimi, D. M. F. van Aalten, R. Brenk, I. H. Gilbert, K. D. Read, A. H. Fairlamb, M. A. J. Ferguson, D. F. Smith, P. G. Wyatt, N-myristoyltransferase inhibitors as new leads to treat sleeping sickness, Nature 464, 728-732 (2010).
19. D. C. Jones, I. Hallyburton, L. Stojanovski, K. D. Read, J. A. Frearson, A. H. Fairlamb, Identification of a kappa-opioid agonist as a potent and selective lead for drug development against human African trypanosomiasis, Biochem. Pharmacol. 80, 1478-1486 (2010).
20. N. Sienkiewicz, H. B. Ong, A. H. Fairlamb, Trypanosoma brucei pteridine reductase 1 is essential for survival in vitro and for virulence in mice, Mol. Microbiol. 77, 658-671 (2010).
21. A. Y. Sokolova, S. Wyllie, S. Patterson, S. L. Oza, K. D. Read, A. H. Fairlamb, Cross-resistance to nitro drugs and implications for treatment of human African trypanosomiasis, Antimicrob. Agents Chemother. 54, 2893-2900 (2010).
22. S. Wyllie, G. Mandal, N. Singh, S. Sundar, A. H. Fairlamb, M. Chatterjee, Elevated levels of tryparedoxin peroxidase in antimony unresponsive Leishmania donovani field isolates, Mol. Biochem. Parasitol. 173, 162-164 (2010).
In collaboration with pharmacologists in the Drug Discovery Unit my group has identified the nitro-drug, fexinidazole, as a promising new oral treatment for visceral leishmaniasis. Based on these findings, a Phase II clinical trial is planned by the Drugs for Neglected Diseases initiative (DNDi) to determine the efficacy and safety of fexinidazole in visceral leishmaniasis patients in Africa. As a backup, we have discovered another nitro-compound, R-PA824, as a potential pre-clinical candidate for this disease. Although S-PA824 is currently in Phase II clinical trials for tuberculosis by the TB Alliance, additional work is required to ensure safety and tolerability of the other enantiomer.