Disparities in drug sensitivity of T. congolense and brucei group trypanosomes is related to differences in adenosine transporters and aquagyceroporins

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Authors

M A Ungogo3; M J Natto1; G D Campagnaro4; A H Alghamdi2; H P de Koning1
1 Institute of Infection, Immunity and Inflammation, University of Glasgow, UK;  2 Institute of Infection, Immunity and Inflammation, University of Glasgow, United Kingdom, UK;  3 Institute of Infection, Immunity and Inflammation, UK;  4 Institute of Infection, Immunity & Inflammation, University of Glasgow, UK

Discussion

Control ofAfrican Animal Trypanosomiasis (AAT) is seriously undermined by the challenge of drug resistance. Trypanosoma brucei, one of the three species that cause AAT, has been extensively studied, and the mechanism of drug resistance in this species depend mostly on mutations in transmembrane transporters that import the drugs. However, advances in molecular parasitology have revealed enormous genetic differences between T. brucei and other animal trypanosomes especially T. congolense. Thus, there is need to understand the genetic and molecular basis of drug resistance in T. congolense in order to aid rational drug design and development and verify whether the brucei models apply. Drug sensitivity assays showed that the EC50s of diminazene aceturate and melarsominein T. congolense were 3 and 20 times higher than in T. brucei, respectively. In addition, T. congolense was 151 times less sensitive to pentamidine and 296 times resistant to suramin relative to T. brucei. It is hypothesised that lack of authentic orthologues of some T. brucei transporters (TbAQP2, TbAT1, and a lysosomal MFST) is responsible for low sensitivity to these drugs in T. congolense. Expression of T. brucei AQP2 (TbAQP2) in T. congolense resulted in an approximately 8-fold increase in sensitivity to pentamidine and 6-fold increase in sensitivity to melarsomine compared to wild type. The T. congolense + TbAQP2 also displayed a higher rate of uptake of [3H]-pentamidine, as well as faster lysis when exposed to melarsomine. On the other hand, T. congolense clones expressing T. brucei P2 adenosine transporter (TbAT1) show a 30-fold increased sensitivity to melarsomine and a 12-fold increase in sensitivity to diminazene, pentamidine and isometamidium. In addition, there is a higher uptake of [3H]-diminazene and [3H]-pentamidine in T. congolense clones expressing TbAT1 compared to the wild type. This indicates that differences in transporters between Trypanosoma species play important role in differential sensitivity and should be considered in the development of new drugs for AAT.

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