Characterisation of pentamidine-resistant Trypanosoma brucei brucei

Mol Biochem Parasitol. 1995 Feb;69(2):289-98. doi: 10.1016/0166-6851(94)00215-9.


Following selection in vitro by exposure to increasing concentrations of the aromatic diamidine pentamidine, a Trypanosoma brucei brucei clone has been characterised in vivo and in vitro. The resistant clone, designated T.b. brucei S427/118/PR32.6, was found to be less virulent than the parental clone T.b. bruci S427/118, with an intraperitoneal injection of 2.5 x 10(6) resistant organisms required to produce a course of disease equivalent to 1 x 10(4) sensitive trypanosomes. This lowered virulence is not associated with an increased susceptibility to the host's immune system, and is not due to the in vitro culturing process. The pentamidine-resistant clone was found to be 26- and 4.5-fold resistant to pentamidine in vitro and in vivo, respectively. Although not cross-resistant in vivo to any other aromatic diamidines (stilbamidine, berenil and propamidine), a 2.4-fold increase in resistance to the melaminophenylarsine melarsoprol was observed. While pentamidine completely inhibited uptake of 1 microM [3H]adenosine in the presence of 1 mM inosine, suggesting that pentamidine is transported by the inosine-insensitive P2 transporter, the pentamidine-resistant clone appeared to have a fully functional P2-adenosine transport system. Both resistant and parental cloned lines accumulated approx. 6 nmol pentamidine (10(8) cells)-1 over the course of 3 h, representing an internal concentration of 0.7-1.0 mM. Thus, unlike previously characterised drug-resistant trypanosomes, T.b. brucei PR32.6 is not deficient in drug accumulation, suggesting that other resistance mechanisms are likely to be involved.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adenosine / metabolism
  • Animals
  • Biological Transport, Active / drug effects
  • Drug Resistance
  • Male
  • Mice
  • Pentamidine / pharmacology*
  • Rats
  • Rats, Sprague-Dawley
  • Trypanosoma brucei brucei / drug effects*
  • Trypanosoma brucei brucei / metabolism
  • Trypanosoma brucei brucei / pathogenicity
  • Virulence


  • Pentamidine
  • Adenosine