Abstract
Background
Trypanosoma brucei is the causative agent of Human African Trypanosomiasis (also known as sleeping sickness), a disease causing serious neurological disorders and fatal if left untreated. Due to its lethal pathogenicity, a variety of treatments have been developed over the years, but which have some important limitations such as acute toxicity and parasite resistance. Metabolomics is an innovative tool used to better understand the parasite’s cellular metabolism, and identify new potential targets, modes of action and resistance mechanisms. The metabolomic approach is mainly associated with robust analytical techniques, such as NMR and Mass Spectrometry. Applying these tools to the trypanosome parasite is, thus, useful for providing new insights into the sleeping sickness pathology and guidance towards innovative treatments.
Aim of review
The present review aims to comprehensively describe the T. brucei biology and identify targets for new or commercialized antitrypanosomal drugs. Recent metabolomic applications to provide a deeper knowledge about the mechanisms of action of drugs or potential drugs against T. brucei are highlighted. Additionally, the advantages of metabolomics, alone or combined with other methods, are discussed.
Key scientific concepts of review
Compared to other parasites, only few studies employing metabolomics have to date been reported on Trypanosoma brucei. Published metabolic studies, treatments and modes of action are discussed. The main interest is to evaluate the metabolomics contribution to the understanding of T. brucei’s metabolism.
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References
Ajoko, C., & Steverding, D. (2015). A cultivation method for growing bloodstream forms of Trypanosoma brucei to higher cell density and for longer time. Parasitology Research, 114, 1611–1612. https://doi.org/10.1007/s00436-015-4346-x
Ali, J. A. M., Creek, D. J., Burgess, K., Allison, H. C., Field, M. C., Mäser, P., & De Koning, H. P. (2013). Pyrimidine salvage in Trypanosoma brucei bloodstream forms and the trypanocidal action of halogenated pyrimidiness. Molecular Pharmacology, 83, 439–453. https://doi.org/10.1124/mol.112.082321
Alkhaldi, A. A. M., Creek, D. J., Ibrahim, H., Kim, D.-H., Quashie, N. B., Burgess, K. E., Changtam, C., Barrett, M. P., Suksamrarn, A., & de Koning, H. P. (2015). Potent trypanocidal curcumin analogs bearing a monoenone linker motif act on Trypanosoma brucei by forming an adduct with trypanothione. Molecular Pharmacology, 87, 451–464. https://doi.org/10.1124/mol.114.096016
Allman, E. L., Painter, H. J., Samra, J., Carrasquilla, M., & Llinás, M. (2016). Metabolomic profiling of the malaria box reveals antimalarial target pathways. Antimicrobial Agents and Chemotherapy, 60, 6635–6649. https://doi.org/10.1128/AAC.01224-16
Alsford, S., Eckert, S., Baker, N., Glover, L., Sanchez-Flores, A., Leung, K. F., Turner, D. J., Field, M. C., Berriman, M., & Horn, D. (2012). High-throughput decoding of antitrypanosomal drug efficacy and resistance. Nature, 482, 232–236. https://doi.org/10.1038/nature10771
Aslett, M., Aurrecoechea, C., Berriman, M., Brestelli, J., Brunk, B. P., Carrington, M., Depledge, D. P., Fischer, S., Gajria, B., Gao, X., Gardner, M. J., Gingle, A., Grant, G., Harb, O. S., Heiges, M., Hertz-Fowler, C., Houston, R., Innamorato, F., Iodice, J., … Wang, H. (2010). Drug resistance in African trypanosomiasis: The melarsoprol and pentamidine story. Trends Parasitology, 29, 110–118.
Atan, N. A. D., Koushki, M., Ahmadi, N. A., & Rezaei-Tavirani, M. (2018). Metabolomics-based studies in the field of Leishmania/leishmaniasis. Alex. J. Med., 54, 383–390. https://doi.org/10.1016/j.ajme.2018.06.002
Baker, N., de Koning, H. P., Mäser, P., & Horn, D. (2013). Drug resistance in African trypanosomiasis: the melarsoprol and pentamidine story. Trends in Parasitology, 29(3), 110–118. https://doi.org/10.1016/j.pt.2012.12.005
Bakker, B. M., Michels, P. A. M., Opperdoes, F. R., & Westerhoff, H. V. (1999). What controls glycolysis in bloodstream form Trypanosoma brucei? Journal of Biological Chemistry, 274, 14551–14559. https://doi.org/10.1074/jbc.274.21.14551
Barrett, M. P., Bakker, B. M., & Breitling, R. (2010). Metabolomic systems biology of trypanosomes. Parasitology, 137, 1285–1290. https://doi.org/10.1017/S003118201000017X
Begolo, D., Vincent, I. M., Giordani, F., Pöhner, I., Witty, M. J., Rowan, T. G., Bengaly, Z., Gillingwater, K., Freund, Y., Wade, R. C., Barrett, M. P., & Clayton, C. (2018). The trypanocidal benzoxaborole AN7973 inhibits trypanosome mRNA processing. PLoS Pathogens, 14, e1007315. https://doi.org/10.1371/journal.ppat.1007315
Berninger, M., Schmidt, I., Ponte-Sucre, A., & Holzgrabe, U. (2017). Novel lead compounds in pre-clinical development against African sleeping sickness. MedChemComm, 8, 1872–1890. https://doi.org/10.1039/c7md00280g
Besteiro, S., Biran, M., Biteau, N., Coustou, V., Baltz, T., Canioni, P., & Bringaud, F. (2002). Succinate secreted by Trypanosoma brucei Is produced by a novel and unique glycosomal enzyme, NADH-dependent fumarate reductase. Journal of Biological Chemistry, 277, 38001–38012. https://doi.org/10.1074/jbc.M201759200
Bringaud, F., Biran, M., Millerioux, Y., Wargnies, M., Allmann, S., & Mazet, M. (2015). Combining reverse genetics and nuclear magnetic resonance-based metabolomics unravels trypanosome-specific metabolic pathways. Molecular Microbiology, 96, 917–926. https://doi.org/10.1111/mmi.12990
Burgess, K., Creek, D., Dewsbury, P., Cook, K., & Barrett, M. P. (2011). Semi-targeted analysis of metabolites using capillary-flow ion chromatography coupled to high-resolution mass spectrometry. Rapid Communications in Mass Spectrometry : RCM, 25(22), 3447–3452. https://doi.org/10.1002/rcm.5247
Chaleckis, R., Meister, I., Zhang, P., & Wheelock, C. E. (2019). Challenges, progress and promises of metabolite annotation for LC–MS-based metabolomics. Current Opinion Biotechnology, 55, 44–50. https://doi.org/10.1016/j.copbio.2018.07.010
Chong, J., Soufan, O., Li, C., Caraus, I., Li, S., Bourque, G., Wishart, D. S., & Xia, J. (2018). MetaboAnalyst 4.0: Towards more transparent and integrative metabolomics analysis. Nucleic Acids Research, 46, W486–W494. https://doi.org/10.1093/nar/gky310
Cockram, P. E., Dickie, E. A., Barrett, M. P., & Smith, T. K. (2020). Halogenated tryptophan derivatives disrupt essential transamination mechanisms in bloodstream form Trypanosoma brucei. PLoS Neglected Tropical Diseases, 14, e0008928. https://doi.org/10.1371/journal.pntd.0008928
Creek, D. J., Mazet, M., Achcar, F., Anderson, J., Kim, D.-H., Kamour, R., Morand, P., Millerioux, Y., Biran, M., Kerkhoven, E. J., Chokkathukalam, A., Weidt, S. K., Burgess, K. E. V., Breitling, R., Watson, D. G., Bringaud, F., & Barrett, M. P. (2015). Probing the metabolic network in bloodstream-form Trypanosoma brucei using untargeted metabolomics with stable isotope labelled glucose. PLoS Pathogens, 11, e1004689. https://doi.org/10.1371/journal.ppat.1004689
Creek, D. J., Nijagal, B., Kim, D.-H., Rojas, F., Matthews, K. R., & Barrett, M. P. (2013). Metabolomics guides rational development of a simplified cell culture medium for drug screening against Trypanosoma brucei. Antimicrobial Agents and Chemotherapy, 57, 2768–2779. https://doi.org/10.1128/AAC.00044-13
Crilly, N. P., & Mugnier, M. R. (2021). Thinking outside the blood: Perspectives on tissue-resident Trypanosoma brucei. PLoS Pathogens, 17, e1009866. https://doi.org/10.1371/journal.ppat.1009866
Das, A., Biswas, N., Chakrabarti, S., 2020. Leish-ExP: a database of exclusive proteins from Leishmania parasite. bioRxiv 2020.05.04.076851; doi: https://doi.org/10.1101/2020.05.04.076851
De Koning, H. (2020). The Drugs of Sleeping Sickness: Their Mechanisms of Action and Resistance, and a Brief History. Tropical Medicine Infectious Disease. https://doi.org/10.3390/tropicalmed5010014
Deeks, E. D. (2019). Fexinidazole: First global approval. Drugs, 79, 215–220. https://doi.org/10.1007/s40265-019-1051-6
Dickie, E. A., Giordani, F., Gould, M. K., Mäser, P., Burri, C., Mottram, J. C., Rao, S. P. S., & Barrett, M. P. (2020). New drugs for human African Trypanosomiasis: A twenty first century success story. Tropical Medicine Infectious Disease, 5, 29. https://doi.org/10.3390/tropicalmed5010029
Dona, A. C., Kyriakides, M., Scott, F., Shephard, E. A., Varshavi, D., Veselkov, K., & Everett, J. R. (2016). A guide to the identification of metabolites in NMR-based metabonomics/metabolomics experiments. Computational and Structural Biotechnology Journal, 14, 135–153. https://doi.org/10.1016/j.csbj.2016.02.005
Doyle, M. A., MacRae, J. I., De Souza, D. P., Saunders, E. C., McConville, M. J., & Likić, V. A. (2009). LeishCyc: A biochemical pathways database for Leishmania major. BMC Systems Biology, 3, 57. https://doi.org/10.1186/1752-0509-3-57
Dunn, W. B., Erban, A., Weber, R. J. M., Creek, D. J., Brown, M., Breitling, R., Hankemeier, T., Goodacre, R., Neumann, S., Kopka, J., & Viant, M. R. (2013). Mass appeal: Metabolite identification in mass spectrometry-focused untargeted metabolomics. Metabolomics, 9, 44–66. https://doi.org/10.1007/s11306-012-0434-4
Fairlamb, A. H., & Horn, D. (2018). Melarsoprol resistance in African trypanosomiasis. Trends in Parasitology, 34, 481–492. https://doi.org/10.1016/j.pt.2018.04.002
Fatarova, M., Bellvert, F., Cahoreau, E., Bringaud, F., & Portais, J.-C. (2016). Methods to Investigate Metabolic Systems in Trypanosoma. Comprehensive Analysis of Parasite Biology: From Metabolism to Drug Discovery (pp. 295–320). US: John Wiley & Sons.
Fiehn, O. (2016). Metabolomics by Gas Chromatography-Mass Spectrometry: the combination of targeted and untargeted profiling. Current Protocols in Molecular Biology, 114, 3041–30432.
Fiehn, O., Robertson, D., Griffin, J., van der Werf, M., Nikolau, B., Morrison, N., Sumner, L. W., Hardy, N. W., Taylor, C., Lindon, J. C., Sansone, S. A., & Sansone, S. A. (2007). The metabolomics standards initiative (MSI). Metabolomics, 3(3), 175–178.
Franco, J., Scarone, L., & Comini, M. A. (2018). Chapter Three - Drugs and Drug Resistance in African and American Trypanosomiasis. In M. Botta (Ed.), Annual Reports in Medicinal Chemistry, Neglected Diseases: Extensive Space for Modern Drug Discovery (pp. 97–133). US: Academic Press.
Frearson, J. A., Brand, S., McElroy, S. P., Cleghorn, L. A. T., Smid, O., Stojanovski, L., Price, H. P., Guther, M. L. S., 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. F., … Wyatt, P. G. (2010). N-Myristoyltransferase inhibitors as new leads to treat sleeping sickness. Nature, 464, 728–732. https://doi.org/10.1038/nature08893
Fridberg, A., Olson, C. L., Nakayasu, E. S., Tyler, K. M., Almeida, I. C., & Engman, D. M. (2008). Sphingolipid synthesis is necessary for kinetoplast segregation and cytokinesis in Trypanosoma brucei. Journal of Cell Science, 121, 522–535. https://doi.org/10.1242/jcs.016741
Giacomoni, F., Le Corguillé, G., Monsoor, M., Landi, M., Pericard, P., Pétéra, M., Duperier, C., Tremblay-Franco, M., Martin, J.-F., Jacob, D., Goulitquer, S., Thévenot, E. A., & Caron, C. (2015). Workflow4Metabolomics: A collaborative research infrastructure for computational metabolomics. Bioinformatics, 31, 1493–1495. https://doi.org/10.1093/bioinformatics/btu813
Grapov, D., Wanichthanarak, K., & Fiehn, O. (2015). MetaMapR: Pathway independent metabolomic network analysis incorporating unknowns. Bioinforma. Oxf. Engl., 31, 2757–2760. https://doi.org/10.1093/bioinformatics/btv194
Grishin, N. V., Osterman, A. L., Brooks, H. B., Phillips, M. A., & Goldsmith, E. J. (1999). X-ray structure of ornithine decarboxylase from Trypanosoma brucei: The native structure and the structure in complex with alpha-difluoromethylornithine. Biochemistry, 38, 15174–15184. https://doi.org/10.1021/bi9915115
Gu, X., Reid, D., Higham, D. J., & Gilbert, D. (2013). Mathematical modelling of polyamine metabolism in bloodstream-form Trypanosoma brucei: An application to drug target identification. PLoS ONE. https://doi.org/10.1371/journal.pone.0053734
Gualdrón-López, M., Brennand, A., Hannaert, V., Quiñones, W., Cáceres, A. J., Bringaud, F., Concepción, J. L., & Michels, P. A. M. (2012). When, how and why glycolysis became compartmentalised in the Kinetoplastea. A new look at an ancient organelle. International Journal for Parasitology, 42, 1–20. https://doi.org/10.1016/j.ijpara.2011.10.007
Hannaert, V. (2011). Sleeping sickness pathogen (Trypanosoma brucei) and natural products: Therapeutic targets and screening systems. Planta Medica, 77, 586–597. https://doi.org/10.1055/s-0030-1250411
Harrison, J. R., Brand, S., Smith, V., Robinson, D. A., Thompson, S., Smith, A., Davies, K., Mok, N., Torrie, L. S., Collie, I., Hallyburton, I., Norval, S., Simeons, F. R. C., Stojanovski, L., Frearson, J. A., Brenk, R., Wyatt, P. G., Gilbert, I. H., & Read, K. D. (2018). A molecular hybridization approach for the design of potent, highly selective, and brain-penetrant N-Myristoyltransferase inhibitors. Journal of Medicinal Chemistry, 61, 8374–8389. https://doi.org/10.1021/acs.jmedchem.8b00884
Heby, O., Persson, L., & Rentala, M. (2007). Targeting the polyamine biosynthetic enzymes: A promising approach to therapy of African sleeping sickness, Chagas’ disease, and leishmaniasis. Amino Acids, 33, 359–366. https://doi.org/10.1007/s00726-007-0537-9
Hendriks, E., van Deursen, F. J., Wilson, J., Sarkar, M., Timms, M., & Matthews, K. R. (2000). Life-cycle differentiation in Trypanosoma brucei: Molecules and mutants. Biochemical Society Transactions, 28, 531–536. https://doi.org/10.1042/bst0280531
Hirumi, H., Doyle, J. J., & Hirumi, K. (1977). Cultivation of bloodstream Trypanosoma brucei. Bulletin of the World Health Organization, 55, 405–409.
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., … Don, R. (2011). SCYX-7158, an orally-active Benzoxaborole for the treatment of stage 2 human African trypanosomiasis. PLoS Neglected Tropical Diseases, 5, e1151. https://doi.org/10.1371/journal.pntd.0001151
Jäger, T., Koch, O., & Flohé, L. (2013). Trypanosomatid Diseases: Molecular Routes to Drug Discovery. US: John Wiley & Sons.
Johnston, K., Kim, D.-H., Kerkhoven, E. J., Burchmore, R., Barrett, M. P., & Achcar, F. (2019). Mapping the metabolism of five amino acids in bloodstream form Trypanosoma brucei using U-13C-labelled substrates and LC-MS. Bioscience Reports. https://doi.org/10.1042/BSR20181601
Kamal, N., Viegelmann, C. V., Clements, C. J., & Edrada-Ebel, R. (2017). Metabolomics-guided isolation of anti-trypanosomal metabolites from the endophytic fungus Lasiodiplodia theobromae. Planta Medica, 83, 565–573. https://doi.org/10.1055/s-0042-118601
Kamleh, M. A., Hobani, Y., Dow, J. A., & Watson, D. G. (2008). Metabolomic profiling of Drosophila using liquid chromatography Fourier transform mass spectrometry. FEBS Letters, 582(19), 2916–2922. https://doi.org/10.1016/j.febslet.2008.07.029
Kanehisa, M., & Goto, S. (2000). KEGG: Kyoto encyclopedia of genes and genomes. Nucleic Acids Research, 28, 27–30.
Kerkhoven, E. J., Achcar, F., Alibu, V. P., Burchmore, R. J., Gilbert, I. H., Trybiło, M., Driessen, N. N., Gilbert, D., Breitling, R., Bakker, B. M., & Barrett, M. P. (2013). Handling uncertainty in dynamic models: The pentose phosphate pathway in Trypanosoma brucei. PLoS Computational Biology, 9, e1003371. https://doi.org/10.1371/journal.pcbi.1003371
Kim, D.-H., Achcar, F., Breitling, R., Burgess, K. E., & Barrett, M. P. (2015). LC–MS-based absolute metabolite quantification: Application to metabolic flux measurement in trypanosomes. Metabolomics, 11, 1721–1732. https://doi.org/10.1007/s11306-015-0827-2
Kovářová, J., Nagar, R., Faria, J., Ferguson, M. A. J., Barrett, M. P., & Horn, D. (2018). Gluconeogenesis using glycerol as a substrate in bloodstream-form Trypanosoma brucei. PLoS Pathogens. https://doi.org/10.1371/journal.ppat.1007475
Kubata, B. K., Duszenko, M., Kabututu, Z., Rawer, M., Szallies, A., Fujimori, K., Inui, T., Nozaki, T., Yamashita, K., Horii, T., Urade, Y., & Hayaishi, O. (2000). Identification of a novel prostaglandin f(2alpha) synthase in Trypanosoma brucei. Journal of Experimental Medicine, 192, 1327–1338. https://doi.org/10.1084/jem.192.9.1327
Lamour, N., Riviere, L., Coustou, V., Coombs, G. H., Barrett, M. P., & Bringaud, F. (2005). Proline metabolism in procyclic Trypanosoma brucei is down-regulated in the presence of glucose. J Biol Chem, 280, 11902–11910.
Leroux, A. E., & Krauth-Siegel, R. L. (2016). Thiol redox biology of trypanosomatids and potential targets for chemotherapy. Molecular and Biochemical Parasitology, 206, 67–74. https://doi.org/10.1016/j.molbiopara.2015.11.003
Li, S., Park, Y., Duraisingham, S., Strobel, F. H., Khan, N., Soltow, Q. A., Jones, D. P., & Pulendran, B. (2013). Predicting network activity from high throughput metabolomics. PLoS Computational Biology, 9, e1003123. https://doi.org/10.1371/journal.pcbi.1003123
Linstead, D. J., Klein, R. A., & Cross, G. A. (1977). Threonine catabolism in Trypanosoma brucei. Journal of General Microbiology, 101, 243–251. https://doi.org/10.1099/00221287-101-2-243
Little, J. L., Williams, A. J., Pshenichnov, A., & Tkachenko, V. (2012). Identification of “known unknowns” utilizing accurate mass data and ChemSpider. Journal of the American Society for Mass Spectrometry, 23, 179–185. https://doi.org/10.1007/s13361-011-0265-y
Long, C. P., & Antoniewicz, M. R. (2019). High-resolution 13C metabolic flux analysis. Nature Protocols, 14, 2856–2877. https://doi.org/10.1038/s41596-019-0204-0
Madji Hounoum, B., Blasco, H., Emond, P., & Mavel, S. (2016). Liquid chromatography–high-resolution mass spectrometry-based cell metabolomics: Experimental design, recommendations, and applications. TrAC, Trends in Analytical Chemistry, 75, 118–128. https://doi.org/10.1016/j.trac.2015.08.003
Mantilla, B. S., Marchese, L., Casas-Sánchez, A., Dyer, N. A., Ejeh, N., Biran, M., Bringaud, F., Lehane, M. J., Acosta-Serrano, A., & Silber, A. M. (2017). Proline metabolism is essential for Trypanosoma brucei brucei survival in the tsetse vector. PLoS Pathogens, 13, e1006158. https://doi.org/10.1371/journal.ppat.1006158
Marchese, L., de Nascimento, J. F., Damasceno, F. S., Bringaud, F., Michels, P. A. M., & Silber, A. M. (2018). The uptake and metabolism of amino acids, and their unique role in the biology of pathogenic trypanosomatids. Pathogens, 7, 36.
Matthews, K. R. (2005). The developmental cell biology of Trypanosoma brucei. Journal of Cell Science, 118, 283–290. https://doi.org/10.1242/jcs.01649
Mazet, M., Morand, P., Biran, M., Bouyssou, G., Courtois, P., Daulouède, S., Millerioux, Y., Franconi, J.-M., Vincendeau, P., Moreau, P., & Bringaud, F. (2013). Revisiting the central metabolism of the bloodstream forms of Trypanosoma brucei: Production of acetate in the mitochondrion is essential for parasite viability. PLoS Neglected Tropical Diseases, 7, e2587. https://doi.org/10.1371/journal.pntd.0002587
Michels, P. A. M., Villafraz, O., Pineda, E., Alencar, M. B., Cáceres, A. J., Silber, A. M., & Bringaud, F. (2021). Carbohydrate metabolism in trypanosomatids: New insights revealing novel complexity, diversity and species-unique features. Experimental Parasitology, 224, 108102. https://doi.org/10.1016/j.exppara.2021.108102
Millerioux, Y., Ebikeme, C., Biran, M., Morand, P., Bouyssou, G., Vincent, I. M., Mazet, M., Riviere, L., Franconi, J.-M., Burchmore, R. J. S., Moreau, P., Barrett, M. P., & Bringaud, F. (2013). The threonine degradation pathway of the Trypanosoma brucei procyclic form: The main carbon source for lipid biosynthesis is under metabolic control. Molecular Microbiology, 90, 114–129. https://doi.org/10.1111/mmi.12351
Mochizuki, K., Inaoka, D. K., Mazet, M., Shiba, T., Fukuda, K., Kurasawa, H., Millerioux, Y., Boshart, M., Balogun, E. O., Harada, S., Hirayama, K., Bringaud, F., & Kita, K. (2020). The ASCT/SCS cycle fuels mitochondrial ATP and acetate production in Trypanosoma brucei. Biochimica Et Biophysica Acta, Bioenergetics, 1861, 148283. https://doi.org/10.1016/j.bbabio.2020.148283
Nok, A. J. (2003). Arsenicals (melarsoprol), pentamidine and suramin in the treatment of human African trypanosomiasis. Parasitology Research, 90, 71–79. https://doi.org/10.1007/s00436-002-0799-9
Nolan, D. P., Rolin, S., Rodriguez, J. R., Abbeele, J. V. D., & Pays, E. (2000). Slender and stumpy bloodstream forms of Trypanosoma brucei display a differential response to extracellular acidic and proteolytic stress. European Journal of Biochemistry, 267, 18–27. https://doi.org/10.1046/j.1432-1327.2000.00935.x
Pineda, E., Thonnus, M., Mazet, M., Mourier, A., Cahoreau, E., Kulyk, H., Dupuy, J.-W., Biran, M., Masante, C., Allmann, S., Rivière, L., Rotureau, B., Portais, J.-C., & Bringaud, F. (2018). Glycerol supports growth of the Trypanosoma brucei bloodstream forms in the absence of glucose: Analysis of metabolic adaptations on glycerol-rich conditions. PLoS Pathogens, 14, e1007412. https://doi.org/10.1371/journal.ppat.1007412
Pinu, F. R., Villas-Boas, S. G., & Aggio, R. (2017). Analysis of intracellular metabolites from microorganisms: Quenching and extraction protocols. Metabolites. https://doi.org/10.3390/metabo7040053
Podolec, P., Szabó, A. H., Blaško, J., Kubinec, R., Górová, R., Višňovský, J., Gnipová, A., Horváth, A., Bierhanzl, V., Hložek, T., & Čabala, R. (2014). Direct silylation of Trypanosoma brucei metabolites in aqueous samples and their GC-MS/MS analysis. Journal of Chromatograpgy, 967, 134–138. https://doi.org/10.1016/j.jchromb.2014.07.023
Price, H. P., Menon, M. R., Panethymitaki, C., Goulding, D., McKean, P. G., & Smith, D. F. (2003). Myristoyl-CoA:Protein N-myristoyltransferase, an essential enzyme and potential drug target in kinetoplastid parasites. Journal of Biological Chemistry, 278, 7206–7214. https://doi.org/10.1074/jbc.M211391200
Richmond, G. S., Gibellini, F., Young, S. A., Major, L., Denton, H., Lilley, A., & Smith, T. K. (2010). Lipidomic analysis of bloodstream and procyclic form Trypanosoma brucei. Parasitology, 137, 1357–1392. https://doi.org/10.1017/S0031182010000715
Rico, E., Rojas, F., Mony, B. M., Szoor, B., MacGregor, P., & Matthews, K. R. (2013). Bloodstream form pre-adaptation to the tsetse fly in Trypanosoma brucei. Front Cell Infect Microbiology. https://doi.org/10.3389/fcimb.2013.00078
Saunders, E. C., Sernee, M. F., Ralton, J. E., & McConville, M. J. (2021). Metabolic stringent response in intracellular stages of Leishmania. Current Opinion in Microbiology, 63, 126–132. https://doi.org/10.1016/j.mib.2021.07.007
Shameer, S., Logan-Klumpler, F. J., Vinson, F., Cottret, L., Merlet, B., Achcar, F., Boshart, M., Berriman, M., Breitling, R., Bringaud, F., Bütikofer, P., Cattanach, A. M., Bannerman-Chukualim, B., Creek, D. J., Crouch, K., de Koning, H. P., Denise, H., Ebikeme, C., Fairlamb, A. H., … Jourdan, F. (2015). TrypanoCyc: A community-led biochemical pathways database for Trypanosoma brucei. Nucleic Acids Research, 43, D637-644. https://doi.org/10.1093/nar/gku944
Smith, C. A., O’Maille, G., Want, E. J., Qin, C., Trauger, S. A., Brandon, T. R., Custodio, D. E., Abagyan, R., & Siuzdak, G. (2005). METLIN: A metabolite mass spectral database. Therapeutic Drug Monitoring, 27, 747–751. https://doi.org/10.1097/01.ftd.0000179845.53213.39
Smith, T. K., & Bütikofer, P. (2010). Lipid metabolism in Trypanosoma brucei. Molecular and Biochemical Parasitology, 172, 66–79. https://doi.org/10.1016/j.molbiopara.2010.04.001
Spinks, D., Smith, V., Thompson, S., Robinson, D. A., Luksch, T., Smith, A., Torrie, L. S., McElroy, S., Stojanovski, L., Norval, S., Collie, I. T., Hallyburton, I., Rao, B., Brand, S., Brenk, R., Frearson, J. A., Read, K. D., Wyatt, P. G., & Gilbert, I. H. (2015). Development of Small-Molecule Trypanosoma brucei N-Myristoyltransferase Inhibitors: Discovery and Optimisation of a Novel Binding Mode. ChemMedChem, 10, 1821–1836. https://doi.org/10.1002/cmdc.201500301
Steketee, P. C., Vincent, I. M., Achcar, F., Giordani, F., Kim, D. H., Creek, D. J., Freund, Y., Jacobs, R., Rattigan, K., Horn, D., Field, M. C., MacLeod, A., & Barrett, M. P. (2018). Benzoxaborole treatment perturbs S-adenosyl-L-methionine metabolism in Trypanosoma brucei. PLoS Neglected Tropical Diseases, 12(5), e0006450. https://doi.org/10.1371/journal.pntd.0006450
Stijlemans, B., De Baetselier, P., Caljon, G., Van Den Abbeele, J., Van Ginderachter, J. A., & Magez, S. (2017). Nanobodies as tools to understand, diagnose, and treat African trypanosomiasis. Frontiers in Immunology. https://doi.org/10.3389/fimmu.2017.00724
Stoessel, D., Nowell, C. J., Jones, A. J., Ferrins, L., Ellis, K. M., Riley, J., Rahmani, R., Read, K. D., McConville, M. J., Avery, V. M., Baell, J. B., & Creek, D. J. (2016). Metabolomics and lipidomics reveal perturbation of sphingolipid metabolism by a novel anti-trypanosomal 3-(oxazolo[4,5-b]pyridine-2-yl)anilide. Metabolomics, 12, 126. https://doi.org/10.1007/s11306-016-1062-1
Sumner, L. W., Amberg, A., Barrett, D., Beale, M. H., Beger, R., Daykin, C. A., Fan, T. W., Fiehn, O., Goodacre, R., Griffin, J. L., Hankemeier, T., Hardy, N., Harnly, J., Higashi, R., Kopka, J., Lane, A. N., Lindon, J. C., Marriott, P., & Viant, M. R. (2007). Proposed minimum reporting standards for chemical analysis Chemical Analysis Working Group (CAWG) Metabolomics Standards Initiative (MSI). Metabolomics : Official Journal of the Metabolomic Society, 3(3), 211–221. https://doi.org/10.1007/s11306-007-0082-2
Tarral, A., Blesson, S., Mordt, O. V., Torreele, E., Sassella, D., Bray, M. A., Hovsepian, L., Evène, E., Gualano, V., Felices, M., & Strub-Wourgaft, N. (2014). Determination of an optimal dosing regimen for fexinidazole, a novel oral drug for the treatment of human African trypanosomiasis: First-in-human studies. Clinical Pharmacokinetics, 53, 565–580. https://doi.org/10.1007/s40262-014-0136-3
Tawfike, A. F., Romli, M., Clements, C., Abbott, G., Young, L., Schumacher, M., Diederich, M., Farag, M., & Edrada-Ebel, R. (2019). Isolation of anticancer and anti-trypanosome secondary metabolites from the endophytic fungus Aspergillus flocculus via bioactivity guided isolation and MS based metabolomics. Journal of Chromatography, 1106–1107, 71–83. https://doi.org/10.1016/j.jchromb.2018.12.032
Torreele, E., Bourdin Trunz, B., Tweats, D., Kaiser, M., Brun, R., Mazué, G., Bray, M. A., & Pécoul, B. (2010). Fexinidazole – A new oral nitroimidazole drug candidate entering clinical development for the treatment of sleeping sickness. PLoS Neglected Tropical Diseases. https://doi.org/10.1371/journal.pntd.0000923
Trindade, S., Rijo-Ferreira, F., Carvalho, T., Pinto-Neves, D., Guegan, F., Aresta-Branco, F., Bento, F., Young, S. A., Pinto, A., Van Den Abbeele, J., Ribeiro, R. M., Dias, S., Smith, T. K., & Figueiredo, L. M. (2016). Trypanosoma brucei parasites occupy and functionally adapt to the adipose tissue in mice. Cell Host & Microbe, 19, 837–848. https://doi.org/10.1016/j.chom.2016.05.002
Uppal, K., Soltow, Q. A., Promislow, D. E. L., Wachtman, L. M., Quyyumi, A. A., & Jones, D. P. (2015). MetabNet: An R package for metabolic association analysis of high-resolution metabolomics data. Front Bioengineer Biotechnology, 3, 87. https://doi.org/10.3389/fbioe.2015.00087
van Hellemond, J. J., & Tielens, A. G. M. (2006). Adaptations in the lipid metabolism of the protozoan parasite Trypanosoma brucei. FEBS Letters, 580, 5552–5558. https://doi.org/10.1016/j.febslet.2006.07.056
Vansterkenburg, E. L., Coppens, I., Wilting, J., Bos, O. J., Fischer, M. J., Janssen, L. H., & Opperdoes, F. R. (1993). The uptake of the trypanocidal drug suramin in combination with low-density lipoproteins by Trypanosoma brucei and its possible mode of action. Acta Tropica, 54, 237–250. https://doi.org/10.1016/0001-706x(93)90096-t
Viant, M. R., Kurland, I. J., Jones, M. R., & Dunn, W. B. (2017). How close are we to complete annotation of metabolomes? Current Opinion in Chemical Biology, 36, 64–69. https://doi.org/10.1016/j.cbpa.2017.01.001
Villafraz, O., Biran, M., Pineda, E., Plazolles, N., Cahoreau, E., Souza, R. O. O., Thonnus, M., Allmann, S., Tetaud, E., Rivière, L., Silber, A. M., Barrett, M. P., Zíková, A., Boshart, M., Portais, J.-C., & Bringaud, F. (2021). Procyclic trypanosomes recycle glucose catabolites and TCA cycle intermediates to stimulate growth in the presence of physiological amounts of proline. PLoS Pathogens, 17, e1009204. https://doi.org/10.1371/journal.ppat.1009204
Vincent, I. M., & Barrett, M. P. (2015). Metabolomic-Based Strategies for Anti-Parasite Drug Discovery. Journal of Biomolecular Screening, 20, 44–55. https://doi.org/10.1177/1087057114551519
Vincent, I. M., Creek, D. J., Burgess, K., Woods, D. J., Burchmore, R. J. S., & Barrett, M. P. (2012). Untargeted metabolomics reveals a lack Of synergy between nifurtimox and eflornithine against Trypanosoma brucei. PLoS Neglected Tropical Diseases. https://doi.org/10.1371/journal.pntd.0001618
Vincent, I. M., Creek, D., Watson, D. G., Kamleh, M. A., Woods, D. J., Wong, P. E., Burchmore, R. J. S., & Barrett, M. P. (2010). A molecular mechanism for Eflornithine resistance in African trypanosomes. PLoS Pathogens. https://doi.org/10.1371/journal.ppat.1001204
Weelden SWH van, Hellemond JJ van, Opperdoes FR, Tielens AGM, (2005) New Functions for Parts of the Krebs Cycle in Procyclic Trypanosoma brucei a Cycle Not Operating as a Cycle. Journal of Biological Chemistry 280: 12451–12460
WHO | Human African trypanosomiasis [WWW Document], n.d. . WHO. URL http://www.who.int/trypanosomiasis_african/en/ (accessed 6.30.20).
Wiedemar, N., Hauser, D. A., & Mäser, P. (2020). 100 Years of Suramin. Antimicrobial Agents and Chemotherapy. https://doi.org/10.1128/AAC.01168-19
Willson, M., Callens, M., Kuntz, D. A., Perié, J., & Opperdoes, F. R. (1993). Synthesis and activity of inhibitors highly specific for the glycolytic enzymes from Trypanosoma brucei. Molecular and Biochemical Parasitology, 59, 201–210. https://doi.org/10.1016/0166-6851(93)90218-m
Wishart, D. S., Tzur, D., Knox, C., Eisner, R., Guo, A. C., Young, N., Cheng, D., Jewell, K., Arndt, D., Sawhney, S., Fung, C., Nikolai, L., Lewis, M., Coutouly, M.-A., Forsythe, I., Tang, P., Shrivastava, S., Jeroncic, K., Stothard, P., … Querengesser, L. (2007). HMDB: The Human Metabolome Database. Nucleic Acids Research, 35, D521-526. https://doi.org/10.1093/nar/gkl923
Zoltner, M., Campagnaro, G. D., Taleva, G., Burrell, A., Cerone, M., Leung, K.-F., Achcar, F., Horn, D., Vaughan, S., Gadelha, C., Zíková, A., Barrett, M. P., de Koning, H. P., & Field, M. C. (2020). Suramin exposure alters cellular metabolism and mitochondrial energy production in African trypanosomes. Journal of Biological Chemistry. https://doi.org/10.1074/jbc.RA120.012355
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Fall, F., Mamede, L., Schioppa, L. et al. Trypanosoma brucei: Metabolomics for analysis of cellular metabolism and drug discovery. Metabolomics 18, 20 (2022). https://doi.org/10.1007/s11306-022-01880-0
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DOI: https://doi.org/10.1007/s11306-022-01880-0