Use this URL to cite or link to this record in EThOS: http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.662612
Title: Investigations on mechanisms of acquisition of drug resistance in trypanosomes
Author: Suswam, E. A.
Awarding Body: University of Edinburgh
Current Institution: University of Edinburgh
Date of Award: 1998
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Abstract:
The study described here was an investigation into the mechanisms of acquisition of drug resistance by Trypanosoma evansi. The main aim was to determine the biochemical basis for the development of resistance to the melaminophenyl arsenical drugs, mel Cy and mel B. Experiments were designed to compare the mode of development of resistance in vitro with in vivo-derived resistance and to determine the effect of host immunity on resistance development. Resistance to mel Cy was induced in a sensitive stock of T. evansi by infection and treatment with sub-curative levels of drug, in immunosuppressed and immunocompetent mice. Induction was also carried out in vitro by cultivation of the culture-adapted T. evansi isolate in the continuous presence of increasing concentrations of mel Cy. Resistance was measured using in vivo drug sensitivity tests and, in vitro growth inhibition assays. High levels (up to 300-fold) of resistance were attained within 6 months of induction in immunosuppressed mice and in vitro. It was not possible to produce resistance in immunocompetent mice, even after 24 months. In vivo drug resistant trypanosomes maintained their infectivity but virulence was reduced. Resistance induced by mel Cy was characterised with respect to stability of resistance and cross resistance to other trypanocides. The resistance developed from either immunosuppressed mice or in vitro continued to be expressed in immunocompetent mice treated with the trypanocidal drug. After withdrawal of drug in vitro-induced resistance remained stable whereas in vivo-derived resistance was reduced by over 50%. Mel Cy-induced resistance conferred cross resistance to other trypanocidal drugs, namely, mel B, Bereniland, to a limited extent, quinapyramine, but not suramin. Sub-populations of trypanosomes naturally resistant to the selection dose (20 ηg/ml) of mel Cy were not found in the unselected parent clone. Increased sensitivity to quinapyramine and suramin was observed after adaptation of the drug sensitive isolate to in vitro culture.
Supervisor: Not available Sponsor: Not available
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID: uk.bl.ethos.662612  DOI: Not available
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