Characterisation of pentamidine-resistant Trypanosoma brucei brucei.
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.
Berger
B J
BJ
Department of Medical Parasitology, London School of Hygiene and Tropical Medicine, UK.
Carter
N S
NS
Fairlamb
A H
AH
D000241:Adenosine / Q000378:metabolism; D000818:Animals; D001693:Biological Transport, Active / Q000187:drug effects; D004351:Drug Resistance; D008297:Male; D051379:Mice; D010419:Pentamidine / Q000494:pharmacology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D014346:Trypanosoma brucei brucei / Q000187:drug effects* / Q000378:metabolism / Q000472:pathogenicity; D014774:Virulence
D010419:Pentamidine; D000241:Adenosine