Partners and International Organizations
(English)
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AT, BE, CZ, DK, FI, FR, DE, HU, IE, IL, IT, LV, NL, NO, PL, PT, RO, SK, ES, SE, CH, TR, UK
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Abstract
(English)
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Trypanosoma brucei is an important human pathogen in Sub-Saharan Africa, where it causes human sleeping sickness. The parasite causes a systemic infection of the human host that inexorably leads to death. About 60 million people in 38 countries are at risk, only a small fraction of which has access to any public health service, diagnosis or treatment. Chemotherapy of human sleeping sickness relies entirely on four old and highly toxic compounds. Melarsoprol (Arsobal®) is the only compound that can be generally used against the late-stage of the disease, i.e. after involvement of the central nervous system. Recently, an alarming rise in melarsoprol resistance has been observed in several regions. Our project adresses the molecular basis of this new type of resistance. Earlier work has demonstrated that the adenosine transporter TbAT1 is involved in melarsoprol uptake, and we have been able to show that many patients with melarsoprol-refractory infections contain parasites with a mutated TbAT1 gene. Genetic deletion of the gene in vitro renders the parasite more resistant to the drug. Further studies have then shown that not only melarsoprol, but also two other trypanocidal drugs, pentamidine and diminazene aceturate, accumulate via this transporter. However, while diminazene aceturate is take up through the TbAT1 transporter exclusively, melarsoprol can also enter the cell via at least one more transporter, HAPT1. The clinically observed resistance to melarsoprol may thus involve at least the loss or the inactivation of two distinct transporters, TbAT1 and HAPT1. In addition to these transporters, we have been able to identify the multidrug-resistance protein TbMRPA as an additional protein that affects melarsoprol resistance. TbMPRA mediates the export of melarsoprol from the cell, and its mutational inactivation also contributes to melarsoprol resistance.
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