Hostname: page-component-78c5997874-fbnjt Total loading time: 0 Render date: 2024-11-17T17:21:59.205Z Has data issue: false hasContentIssue false
  • English
  • Français

High-throughput decoding of drug targets and drug resistance mechanisms in African trypanosomes

Published online by Cambridge University Press:  08 April 2013

DAVID HORN
DAVID HORN*
Affiliation:
London School of Hygiene and Tropical Medicine, Keppel Street, London WC1E 7HT, UK
*
Corresponding author: London School of Hygiene and Tropical Medicine, Keppel Street, London WC1E 7HT, UK. Tel: +44 20 7927 2352. Fax: +44 20 7636 8739. E-mail: [email protected]
Get access Rights & Permissions [Opens in a new window]

Summary

The availability of genome sequence data has facilitated the development of high-throughput genetic screening approaches in microbial pathogens. In the African trypanosome, Trypanosoma brucei, genome-scale RNA interference screens have proven particularly effective in this regard. These genetic screens allow for identification of the genes that contribute to a particular pathway or mechanisms of interest. The approach has been used to assess loss-of-fitness, revealing the genes and proteins required for parasite viability and growth. The outputs from these screens predict essential and dispensable genes and facilitate drug target prioritization efforts. The approach has also been used to assess resistance to anti-trypanosomal drugs, revealing the genes and proteins that facilitate drug uptake and action. These outputs also highlight likely mechanisms underlying clinically relevant drug resistance. I first review these findings in the context of what we know about current drugs. I then describe potential contributions that these high-throughput approaches could make to the development and implementation of new drugs.

Keywords

LeishmaniaRIT-seqRNA interferenceTrypanosoma bruceiTrypanosoma cruzi
Type
Research Article
Information
Parasitology , Volume 141 , Issue 1: Symposia of the British Society for Parasitology volume 49 Emerging paradigms in anti-infective drug design , January 2014 , pp. 77 - 82
Copyright
Copyright © Cambridge University Press 2013 

Access options

Get access to the full version of this content by using one of the access options below. (Log in options will check for institutional or personal access. Content may require purchase if you do not have access.)

References

REFERENCES

Alsford, S., Turner, D. J., Obado, S. O., Sanchez-Flores, A., Glover, L., Berriman, M., Hertz-Fowler, C. and Horn, D. (2011). High-throughput phenotyping using parallel sequencing of RNA interference targets in the African trypanosome. Genome Research 21, 915–924.CrossRefGoogle ScholarPubMed
Alsford, S., Eckert, S., Baker, N., Glover, L., Sanchez-Flores, A., Leung, K. F., Turner, D. J., Field, M. C., Berriman, M. and Horn, D. (2012). High-throughput decoding of antitrypanosomal drug efficacy and resistance. Nature 482, 232–236. doi: 10.1038/nature10771.Google Scholar
Bacchi, C. J., Nathan, H. C., Hutner, S. H., Mccann, P. P. and Sjoerdsma, A. (1980). Polyamine metabolism: a potential therapeutic target in trypanosomes. Science 210, 332–334.Google Scholar
Baker, N., Alsford, S. and Horn, D. (2011). Genome-wide RNAi screens in African trypanosomes identify the nifurtimox activator NTR and the eflornithine transporter AAT6. Molecular and Biochemical Parasitology 176, 55–57.CrossRefGoogle ScholarPubMed
Baker, N., Glover, L., Munday, J. C., Aguinaga Andres, D., Barrett, M. P., De Koning, H. P. and Horn, D. (2012). Aquaglyceroporin 2 controls susceptibility to melarsoprol and pentamidine in African trypanosomes. Proceedings of the National Academy of Sciences, USA 109, 10996–11001. doi: 1202885109 [pii] 10.1073/pnas.1202885109Google Scholar
Berriman, M., Ghedin, E., Hertz-Fowler, C., Blandin, G., Renauld, H., Bartholomeu, D. C., Lennard, N. J., Caler, E., Hamlin, N. E., Haas, B., Bohme, U., Hannick, L., Aslett, M. A., Shallom, J., Marcello, L., Hou, L., Wickstead, B., Alsmark, U. C., Arrowsmith, C., Atkin, R. J., Barron, A. J., Bringaud, F., Brooks, K., Carrington, M., Cherevach, I., Chillingworth, T. J., Churcher, C., Clark, L. N., Corton, C. H., Cronin, A., Davies, R. M., Doggett, J., Djikeng, A., Feldblyum, T., Field, M. C., Fraser, A., Goodhead, I., Hance, Z., Harper, D., Harris, B. R., Hauser, H., Hostetler, J., Ivens, A., Jagels, K., Johnson, D., Johnson, J., Jones, K., Kerhornou, A. X., Koo, H., Larke, N., Landfear, S., Larkin, C., Leech, V., Line, A., Lord, A., Macleod, A., Mooney, P. J., Moule, S., Martin, D. M., Morgan, G. W., Mungall, K., Norbertczak, H., Ormond, D., Pai, G., Peacock, C. S., Peterson, J., Quail, M. A., Rabbinowitsch, E., Rajandream, M. A., Reitter, C., Salzberg, S. L., Sanders, M., Schobel, S., Sharp, S., Simmonds, M., Simpson, A. J., Tallon, L., Turner, C. M., Tait, A., Tivey, A. R., Van Aken, S., Walker, D., Wanless, D., Wang, S., White, B., White, O., Whitehead, S., Woodward, J., Wortman, J., Adams, M. D., Embley, T. M., Gull, K., Ullu, E., Barry, J. D., Fairlamb, A. H., Opperdoes, F., Barrell, B. G., Donelson, J. E., Hall, N., Fraser, C. M., Melville, S. E. and El-Sayed, N. M. (2005). The genome of the African trypanosome Trypanosoma brucei. Science 309, 416–422.Google Scholar
Brun, R., Blum, J., Chappuis, F. and Burri, C. (2010). Human African trypanosomiasis. Lancet 375, 148–159.CrossRefGoogle ScholarPubMed
Ehrlich, P. (1913). Address in pathology, on chemotherapy: delivered before the Seventeenth International Congress of Medicine. British Medical Journal 2, 353–359.Google Scholar
El-Sayed, N. M., Myler, P. J., Bartholomeu, D. C., Nilsson, D., Aggarwal, G., Tran, A. N., Ghedin, E., Worthey, E. A., Delcher, A. L., Blandin, G., Westenberger, S. J., Caler, E., Cerqueira, G. C., Branche, C., Haas, B., Anupama, A., Arner, E., Aslund, L., Attipoe, P., Bontempi, E., Bringaud, F., Burton, P., Cadag, E., Campbell, D. A., Carrington, M., Crabtree, J., Darban, H., Da Silveira, J. F., De Jong, P., Edwards, K., Englund, P. T., Fazelina, G., Feldblyum, T., Ferella, M., Frasch, A. C., Gull, K., Horn, D., Hou, L., Huang, Y., Kindlund, E., Klingbeil, M., Kluge, S., Koo, H., Lacerda, D., Levin, M. J., Lorenzi, H., Louie, T., Machado, C. R., Mcculloch, R., Mckenna, A., Mizuno, Y., Mottram, J. C., Nelson, S., Ochaya, S., Osoegawa, K., Pai, G., Parsons, M., Pentony, M., Pettersson, U., Pop, M., Ramirez, J. L., Rinta, J., Robertson, L., Salzberg, S. L., Sanchez, D. O., Seyler, A., Sharma, R., Shetty, J., Simpson, A. J., Sisk, E., Tammi, M. T., Tarleton, R., Teixeira, S., Van Aken, S., Vogt, C., Ward, P. N., Wickstead, B., Wortman, J., White, O., Fraser, C. M., Stuart, K. D. and Andersson, B. (2005). The genome sequence of Trypanosoma cruzi, etiologic agent of Chagas disease. Science 309, 409–415. doi: 10.1126/science.1112631.Google Scholar
Frearson, J. A., Brand, S., Mcelroy, S. P., Cleghorn, L. A., Smid, O., Stojanovski, L., Price, H. P., Guther, M. L., Torrie, L. S., Robinson, D. A., Hallyburton, I., Mpamhanga, C. P., Brannigan, J. A., Wilkinson, A. J., Hodgkinson, M., Hui, R., Qiu, W., Raimi, O. G., Van Aalten, D. M., Brenk, R., Gilbert, I. H., Read, K. D., Fairlamb, A. H., Ferguson, M. A., Smith, D. F. and Wyatt, P. G. (2010). N-myristoyltransferase inhibitors as new leads to treat sleeping sickness. Nature 464, 728–732. doi: nature08893 [pii] 10.1038/nature08893.Google Scholar
Hall, B. S., Bot, C. and Wilkinson, S. R. (2011). Nifurtimox activation by trypanosomal type I nitroreductases generates cytotoxic nitrile metabolites. Journal of Biological Chemistry 286, 13088–13095. doi: M111.230847 [pii] 10.1074/jbc.M111.230847.Google Scholar
Hopkins, A. L. (2008). Network pharmacology: the next paradigm in drug discovery. Nature Chemical Biology 4, 682–690. doi: nchembio.118 [pii] 10.1038/nchembio.118.Google Scholar
Horn, D. and McCulloch, R. (2010). Molecular mechanisms underlying the control of antigenic variation in African trypanosomes. Current Opinion in Microbiology 13, 700–705. doi: S1369-5274(10)00123-2 [pii] 10.1016/j.mib.2010.08.009.CrossRefGoogle ScholarPubMed
Ivens, A. C., Peacock, C. S., Worthey, E. A., Murphy, L., Aggarwal, G., Berriman, M., Sisk, E., Rajandream, M. A., Adlem, E., Aert, R., Anupama, A., Apostolou, Z., Attipoe, P., Bason, N., Bauser, C., Beck, A., Beverley, S. M., Bianchettin, G., Borzym, K., Bothe, G., Bruschi, C. V., Collins, M., Cadag, E., Ciarloni, L., Clayton, C., Coulson, R. M., Cronin, A., Cruz, A. K., Davies, R. M., De Gaudenzi, J., Dobson, D. E., Duesterhoeft, A., Fazelina, G., Fosker, N., Frasch, A. C., Fraser, A., Fuchs, M., Gabel, C., Goble, A., Goffeau, A., Harris, D., Hertz-Fowler, C., Hilbert, H., Horn, D., Huang, Y., Klages, S., Knights, A., Kube, M., Larke, N., Litvin, L., Lord, A., Louie, T., Marra, M., Masuy, D., Matthews, K., Michaeli, S., Mottram, J. C., Muller-Auer, S., Munden, H., Nelson, S., Norbertczak, H., Oliver, K., O'Neil, S., Pentony, M., Pohl, T. M., Price, C., Purnelle, B., Quail, M. A., Rabbinowitsch, E., Reinhardt, R., Rieger, M., Rinta, J., Robben, J., Robertson, L., Ruiz, J. C., Rutter, S., Saunders, D., Schafer, M., Schein, J., Schwartz, D. C., Seeger, K., Seyler, A., Sharp, S., Shin, H., Sivam, D., Squares, R., Squares, S., Tosato, V., Vogt, C., Volckaert, G., Wambutt, R., Warren, T., Wedler, H., Woodward, J., Zhou, S., Zimmermann, W., Smith, D. F., Blackwell, J. M., Stuart, K. D., Barrell, B. and Myler, P. J. (2005). The genome of the kinetoplastid parasite, Leishmania major. Science 309, 436–442. doi: 10.1126/science.1112680.Google Scholar
Jacobs, R. T., Nare, B., Wring, S. A., Orr, M. D., Chen, D., Sligar, J. M., Jenks, M. X., Noe, R. A., Bowling, T. S., Mercer, L. T., Rewerts, C., Gaukel, E., Owens, J., Parham, R., Randolph, R., Beaudet, B., Bacchi, C. J., Yarlett, N., Plattner, J. J., Freund, Y., Ding, C., Akama, T., Zhang, Y. K., Brun, R., Kaiser, M., Scandale, I. and Don, R. (2011). SCYX-7158, an orally-active benzoxaborole for the treatment of stage 2 human African trypanosomiasis. PLoS Neglected Tropical Diseases 5, e1151. doi: 10.1371/journal.pntd.0001151 PNTD-D-10-00094 [pii].Google Scholar
Kaiser, M., Bray, M. A., Cal, M., Bourdin Trunz, B., Torreele, E. and Brun, R. (2011). Antitrypanosomal activity of fexinidazole, a new oral nitroimidazole drug candidate for treatment of sleeping sickness. Antimicrobial Agents and Chemotherapy 55, 5602–5608. doi: AAC.00246-11 [pii] 10.1128/AAC.00246-11.CrossRefGoogle ScholarPubMed
MacGregor, P., Szoor, B., Savill, N. J. and Matthews, K. R. (2012). Trypanosomal immune evasion, chronicity and transmission: an elegant balancing act. Nature Reviews Microbiology 10, 431–438. doi: nrmicro2779 [pii] 10.1038/nrmicro2779.Google Scholar
Magarinos, M. P., Carmona, S. J., Crowther, G. J., Ralph, S. A., Roos, D. S., Shanmugam, D., Van Voorhis, W. C. and Aguero, F. (2012). TDR targets: a chemogenomics resource for neglected diseases. Nucleic Acids Research 40, D1118–D1127. doi: gkr1053 [pii] 10.1093/nar/gkr1053.Google Scholar
Maser, P., Sutterlin, C., Kralli, A. and Kaminsky, R. (1999). A nucleoside transporter from Trypanosoma brucei involved in drug resistance. Science 285, 242–244.CrossRefGoogle ScholarPubMed
Morris, J. C., Wang, Z., Drew, M. E. and Englund, P. T. (2002). Glycolysis modulates trypanosome glycoprotein expression as revealed by an RNAi library. EMBO Journal 21, 4429–4438.Google Scholar
Ngo, H., Tschudi, C., Gull, K. and Ullu, E. (1998). Double-stranded RNA induces mRNA degradation in Trypanosoma brucei. Proceedings of the National Academy of Sciences, USA 95, 14687–14692.Google Scholar
Pepin, J. and Milord, F. (1994). The treatment of human African trypanosomiasis. Advances in Parasitology 33, 1–47.CrossRefGoogle ScholarPubMed
Priotto, G., Kasparian, S., Mutombo, W., Ngouama, D., Ghorashian, S., Arnold, U., Ghabri, S., Baudin, E., Buard, V., Kazadi-Kyanza, S., Ilunga, M., Mutangala, W., Pohlig, G., Schmid, C., Karunakara, U., Torreele, E. and Kande, V. (2009). Nifurtimox-eflornithine combination therapy for second-stage African Trypanosoma brucei gambiense trypanosomiasis: a multicentre, randomised, phase III, non-inferiority trial. Lancet 374, 56–64. doi: S0140-6736(09)61117-X [pii] 10.1016/S0140-6736(09)61117-X.Google Scholar
Roy Chowdhury, A., Bakshi, R., Wang, J., Yildirir, G., Liu, B., Pappas-Brown, V., Tolun, G., Griffith, J. D., Shapiro, T. A., Jensen, R. E. and Englund, P. T. (2010). The killing of African trypanosomes by ethidium bromide. PLoS Pathogenesis 6, e1001226. doi: 10.1371/journal.ppat.1001226.Google Scholar
Schumann Burkard, G., Jutzi, P. and Roditi, I. (2011). Genome-wide RNAi screens in bloodstream form trypanosomes identify drug transporters. Molecular and Biochemical Parasitology 175, 91–94.Google Scholar
Shapiro, T. A. and Englund, P. T. (1990). Selective cleavage of kinetoplast DNA minicircles promoted by antitrypanosomal drugs. Proceedings of the National Academy of Sciences, USA 87, 950–954.Google Scholar
Stewart, M. L., Krishna, S., Burchmore, R. J., Brun, R., De Koning, H. P., Boykin, D. W., Tidwell, R. R., Hall, J. E. and Barrett, M. P. (2005). Detection of arsenical drug resistance in Trypanosoma brucei with a simple fluorescence test. Lancet 366, 486–487. doi: S0140-6736(05)66793-1 [pii] 10.1016/S0140-6736(05)66793-1.Google Scholar
Vanhollebeke, B. and Pays, E. (2010). The trypanolytic factor of human serum: many ways to enter the parasite, a single way to kill. Molecular Microbiology 76, 806–814. doi: MMI7156 [pii] 10.1111/j.1365-2958.2010.07156.x.Google Scholar
Vincent, I. M., Creek, D., Watson, D. G., Kamleh, M. A., Woods, D. J., Wong, P. E., Burchmore, R. J. and Barrett, M. P. (2010). A molecular mechanism for eflornithine resistance in African trypanosomes. PLoS Pathogenesis 6, e1001204.Google Scholar
Wilkinson, S. R., Taylor, M. C., Horn, D., Kelly, J. M. and Cheeseman, I. (2008). A mechanism for cross-resistance to nifurtimox and benznidazole in trypanosomes. Proceedings of the National Academy of Sciences, USA 105, 5022–5027.Google Scholar
Wilson, W. D., Tanious, F. A., Mathis, A., Tevis, D., Hall, J. E. and Boykin, D. W. (2008). Antiparasitic compounds that target DNA. Biochimie 90, 999–1014. doi: S0300-9084(08)00051-5 [pii] 10.1016/j.biochi.2008.02.017.Google Scholar
Wyllie, S., Patterson, S. and Fairlamb, A. H. (2012). Assessing the essentiality of Leishmania donovani nitroreductase and its role in nitro-drug activation. Antimicrobial Agents and Chemotherapy doi: AAC.01788-12 [pii] 10.1128/AAC.01788-12.Google Scholar