scholarly journals The Trypanocide Diminazene Aceturate Is Accumulated Predominantly through the TbAT1 Purine Transporter: Additional Insights on Diamidine Resistance in African Trypanosomes

2004 ◽  
Vol 48 (5) ◽  
pp. 1515-1519 ◽  
Author(s):  
Harry P. de Koning ◽  
Laura F. Anderson ◽  
Mhairi Stewart ◽  
Richard J. S. Burchmore ◽  
Lynsey J. M. Wallace ◽  
...  
Keyword(s):  
Cell Line ◽  
Trypanosoma Brucei ◽  
Domestic Animals ◽  
Trypanosoma Brucei Brucei ◽  
Diminazene Aceturate ◽  
Severe Problem ◽  
African Trypanosomes ◽  
Detectable Rate ◽  
Almost All ◽  
Null Mutants

ABSTRACT Resistance to diminazene aceturate (Berenil) is a severe problem in the control of African trypanosomiasis in domestic animals. It has been speculated that resistance may be the result of reduced diminazene uptake by the parasite. We describe here the mechanisms by which [3H]diminazene is transported by Trypanosoma brucei brucei bloodstream forms. Diminazene was rapidly accumulated through a single transporter, with a Km of 0.45 ± 0.11 μM, which was dose dependently inhibited by pentamidine and adenosine. The Ki values for these inhibitors were consistent with this transporter being the P2/TbAT1 adenosine transporter. Yeast expressing TbAT1 acquired the ability to take up [3H]diminazene and [3H]pentamidine. TbAT1-null mutants had lost almost all capacity for [3H]diminazene transport. However, this cell line still displayed a small but detectable rate of [3H]diminazene accumulation, in a nonsaturable manner. We conclude that TbAT1 mediates [3H]diminazene transport almost exclusively and that this explains the observed diminazene resistance phenotypes of TbAT1-null mutants and field isolates.

scholarly journals In Vitro Generation of Human High-Density-Lipoprotein-Resistant Trypanosoma brucei brucei

2006 ◽  
Vol 5 (8) ◽  
pp. 1276-1286 ◽  
Author(s):  
Sara D. Faulkner ◽  
Monika W. Oli ◽  
Rudo Kieft ◽  
Laura Cotlin ◽  
Justin Widener ◽  
...  
Keyword(s):  
High Density Lipoprotein ◽  
Trypanosoma Brucei ◽  
Density Lipoprotein ◽  
High Density ◽  
Surface Glycoprotein ◽  
Trypanosoma Brucei Brucei ◽  
African Trypanosomes ◽  
Expression Site ◽  
Human High Density Lipoprotein

ABSTRACT The host range of African trypanosomes is influenced by innate protective molecules in the blood of primates. A subfraction of human high-density lipoprotein (HDL) containing apolipoprotein A-I, apolipoprotein L-I, and haptoglobin-related protein is toxic to Trypanosoma brucei brucei but not the human sleeping sickness parasite Trypanosoma brucei rhodesiense. It is thought that T. b. rhodesiense evolved from a T. b. brucei-like ancestor and expresses a defense protein that ablates the antitrypanosomal activity of human HDL. To directly investigate this possibility, we developed an in vitro selection to generate human HDL-resistant T. b. brucei. Here we show that conversion of T. b. brucei from human HDL sensitive to resistant correlates with changes in the expression of the variant surface glycoprotein (VSG) and abolished uptake of the cytotoxic human HDLs. Complete transcriptome analysis of the HDL-susceptible and -resistant trypanosomes confirmed that VSG switching had occurred but failed to reveal the expression of other genes specifically associated with human HDL resistance, including the serum resistance-associated gene (SRA) of T. b. rhodesiense. In addition, we found that while the original active expression site was still utilized, expression of three expression site-associated genes (ESAG) was altered in the HDL-resistant trypanosomes. These findings demonstrate that resistance to human HDLs can be acquired by T. b. brucei.

Trypanosoma brucei brucei oligopeptidase B null mutants display increased prolyl oligopeptidase-like activity

2012 ◽  
Vol 182 (1-2) ◽  
pp. 7-16 ◽  
Author(s):  
Richard T. Kangethe ◽  
Alain F.V. Boulangé ◽  
Virginie Coustou ◽  
Théo Baltz ◽  
Theresa H.T. Coetzer
Keyword(s):  
Trypanosoma Brucei ◽  
Prolyl Oligopeptidase ◽  
Trypanosoma Brucei Brucei ◽  
Oligopeptidase B ◽  
Null Mutants

scholarly journals Multiple Genetic Mechanisms Lead to Loss of Functional TbAT1 Expression in Drug-Resistant Trypanosomes

2009 ◽  
Vol 9 (2) ◽  
pp. 336-343 ◽  
Author(s):  
Mhairi L. Stewart ◽  
Richard J. S. Burchmore ◽  
Caroline Clucas ◽  
Christiane Hertz-Fowler ◽  
Karen Brooks ◽  
...  
Keyword(s):  
Trypanosoma Brucei ◽  
Drug Resistant ◽  
Diminazene Aceturate ◽  
Content Type ◽  
African Trypanosomes ◽  
Genomic Location ◽  
Adenosine Uptake ◽  
Resistant Lines ◽  
The Status ◽  
Genetic Mechanisms

ABSTRACT The P2 aminopurine transporter, encoded by TbAT1 in African trypanosomes in the Trypanosoma brucei group, carries melaminophenyl arsenical and diamidine drugs into these parasites. Loss of this transporter contributes to drug resistance. We identified the genomic location of TbAT1 to be in the subtelomeric region of chromosome 5 and determined the status of the TbAT1 gene in two trypanosome lines selected for resistance to the melaminophenyl arsenical, melarsamine hydrochloride (Cymelarsan), and in a Trypanosoma equiperdum clone selected for resistance to the diamidine, diminazene aceturate. In the Trypanosoma brucei gambiense STIB 386 melarsamine hydrochloride-resistant line, TbAT1 is deleted, while in the Trypanosoma brucei brucei STIB 247 melarsamine hydrochloride-resistant and T. equiperdum diminazene-resistant lines, TbAT1 is present, but expression at the RNA level is no longer detectable. Further characterization of TbAT1 in T. equiperdum revealed that a loss of heterozygosity at the TbAT1 locus accompanied loss of expression and that P2-mediated uptake of [3H]diminazene is lost in drug-resistant T. equiperdum. Adenine-inhibitable adenosine uptake is still detectable in a ΔTbat1 T. b. brucei mutant, although at a greatly reduced capacity compared to that of the wild type, indicating that an additional adenine-inhibitable adenosine permease, distinct from P2, is present in these cells.

scholarly journals Efficacy of Isometamidiumin Combination with Verapamil, Chlorpromazine ‎or Sodium-ethylenediaminetetra-acetic Acid in Treatment of Experimental ‎Diminazene Aceturate-resistant Strain of Trypanosoma brucei brucei ‎Infection in Rats

2020 ◽  
Vol 17 (4) ◽  
pp. 37-45
Author(s):  
I. C. Chukwudi ◽  
O. C. Omemgboji ◽  
B. M. Anene
Keyword(s):  
Acetic Acid ◽  
Trypanosoma Brucei ◽  
Resistant Strain ◽  
Parasite Clearance ◽  
Negative Control ◽  
Male Rats ◽  
Control Group ◽  
Sprague Dawley ◽  
Trypanosoma Brucei Brucei ◽  
Diminazene Aceturate

This study investigated the efficacy of different chemotherapeutic regimes in the treatment of rats experimentally infected with diminazene aceturate-resistant strain Trypanosoma brucei brucei. Thirty Sprague Dawley male rats used for the study were randomly assigned to six groups of five rats eachas follows: group A-uninfected untreated (negative control), group B-infected and untreated (positive control), groups C-F were infected and treated with 1.0 mg/kg isometamidum chloride, administered intramuscularly on day 11 post-infection. However, rats in groups D, E and F received further treatments with 700 mg/kg sodium-ethylenediamine tetra-acetic acid, 0.4 mg/kg verapamil and 3 mg/kg chlorpromazine, respectively, administered orally for four days. Clearance of parasite post-treatment (PT), mortality PT, relapse parasitaemia post-clearance, body weight change, rectal temperature, packed cell volume (PCV), haemoglobin (HB) concentration and red blood cell count (RBC) were determined during the experiment. Result showed parasite clearance PT of 100% in groups D and E, 80% in group F and 20% in group C by 24 hours PT. The infection relapsed on day 35 PT in 40% of rats in group C, on day 37 PT in 20% of rats in group F and lastly 20% of rats in groups D and E on day 39 PT. Rats that received drug combination showed marginal improvement in erythrocytic parameters analysed when compared with those treatment with isometamidium alone. Combination therapy showed faster clearance of parasite from the blood and also prolonged relapse post-clearance, thus had a better promising efficacy when compared to using isometamiduim chloride alone.

scholarly journals Anti-Trypanosomal Activity of Guiera senegalensis on Trypanosoma brucei Infected Mice

2019 ◽  
Vol 9 (4-s) ◽  
pp. 273-279
Author(s):  
Zongo André ◽  
Vitouley Sèna Hervé ◽  
Bengaly Zakaria ◽  
Kaboré Adama ◽  
Traoré Aristide ◽  
...  
Keyword(s):  
Body Weight ◽  
Acute Toxicity ◽  
Survival Time ◽  
Trypanosoma Brucei ◽  
Oral Route ◽  
Phytochemical Screening ◽  
Trypanosoma Brucei Brucei ◽  
Diminazene Aceturate ◽  
Mean Survival Time ◽  
Guiera Senegalensis

Aqueous decoction of Guiera senegalensis leaves was studied orally and intraperitoneally for its antitrypanosomal activity on mice infected experimentally with Trypanosoma brucei brucei. After a phytochemical screening followed by an acute toxicity study on mice, the extract of plant was administered once daily for 2 days at doses of 60, 120 and 240 mg / kg orally and 15, 30 and 60 mg / kg intraperitoneally after infection. Then, parameters of parasitaemia, packed cell volume (PCV), mean survival time and body weight of the mice treated with the extract were measured and compared with positive (diminazene aceturate) and negative (distilled water) controls for 7 days in a row. Results indicate that the aqueous extract of G. senegalensis leaves contains tannins, flavonoids, saponosides, reducing compounds and anthocyanosides, alkaloids and coumarins. LD50 of the extract are 1264.49 mg / kg by oral route and 316.22 mg / kg by intraperitoneal route. The doses of 240 mg / kg by oral route and 15 and 60 mg / kg by intraperitoneal route of aqueous extract showed a mean survival time (5 days) comparable to the positive control. Parasitaemia level increased in all mice tested except in mice treated with diminazene aceturate during the post-infestation period. During this period, PCV and body weight of all mice decreased by both routes of administration. These results of the study show the pharmacological utility of G. senegalensis leaves in the control of TAA by herders / pastoralists and suggest continuing further bio-guided studies to isolate the active components of the plant in order to improve their efficiency. Keywords: In vivo test; Trypanosoma brucei brucei; Guiera senegalensis leaves; phytochemical screening; acute toxicity.

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