Item Details

Title: Mechanisms of Arsenical and Diamidine Uptake and Resistance in
Trypanosoma brucei

Date Published: 2003
Author/s: Matovu, E., Mhairi, L. S., Geiser, F., Brun, R., Maser, P., Wallace, L. J. M., Burchmore, R., Enyaru, J. C. K., Barret, P., Kaminsky, R., Seebeck, T. and De Koning, H. P.
Data publication:
Funding Agency : e Swiss
National Science Foundation, grant C00.0042 from COST program
B16, the BBSRC (17/C13486), grant 970391 from the UNDP/World
Bank/WHO Special Programme for Research and Training in Tropical
Diseases, and the Wellcome Trust
Copyright/patents/trade marks: American Society for Microbiology
Journal Publisher: Eukaryotic Cell
Affiliation: Institute of Cell Biology, CH-3012 Bern,1 Swiss Tropical Institute, CH-4002 Basel,3 and Novartis Animal Health,
CH-1566 St. Aubin,5 Switzerland; Institute of Biomedical and Life Sciences, University of Glasgow,
Glasgow G12 8QQ, United Kingdom2
; and Livestock Health Research Institute, Tororo, Uganda4
Keywords: Mechanisms, Arsenical, Diamidine, Uptake and Resistance, Trypanosoma brucei


Sleeping sickness, caused by Trypanosoma brucei spp., has become resurgent in sub-Saharan Africa. Moreover, there is an alarming increase in treatment failures with melarsoprol, the principal agent used against
late-stage sleeping sickness. In T. brucei, the uptake of melarsoprol as well as diamidines is thought to be
mediated by the P2 aminopurine transporter, and loss of P2 function has been implicated in resistance to these
agents. The trypanosomal gene TbAT1 has been found to encode a P2-type transporter when expressed in yeast.
Here we investigate the role of TbAT1 in drug uptake and drug resistance in T. brucei by genetic knockout of
TbAT1. Tbat1-null trypanosomes were deficient in P2-type adenosine transport and lacked adenosine-sensitive
transport of pentamidine and melaminophenyl arsenicals. However, the null mutants were only slightly
resistant to melaminophenyl arsenicals and pentamidine, while resistance to other diamidines such as diminazene was more pronounced. Nevertheless, the reduction in drug sensitivity might be of clinical significance,
since mice infected with tbat1-null trypanosomes could not be cured with 2 mg of melarsoprol/kg of body weight
for four consecutive days, whereas mice infected with the parental line were all cured by using this protocol.
Two additional pentamidine transporters, HAPT1 and LAPT1, were still present in the null mutant, and
evidence is presented that HAPT1 may be responsible for the residual uptake of melaminophenyl arsenicals.
High-level arsenical resistance therefore appears to involve the loss of more than one transporter.