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Title: Plasmodium falciparum transporters as antimalarial drug targets
Author: Uhlemann, Anne-Catrin
ISNI:       0000 0004 2723 7374
Awarding Body: St George's, University of London
Current Institution: St George's, University of London
Date of Award: 2011
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Plasmodiumfalciparum malaria poses one of the most important disease problems in the world. Despite decades of effort to improve disease outcome, the emergence and rapid dissemination of multi-drug resistant parasites has led to a disturbing increase in malaria mortality and morbidity. A critical limitation in managing multi-drug resistant falciparum malaria has been the incomplete understanding of both the underlying molecular mechanisms of drug resistance and the mode of action of widely used drugs. This study aimed to characterise the molecular mechanisms underlying multi- drug resistant malaria by studying the role of gene amplification in the P. falciparum multi-drug resistance gene 1 (pfmdrl) in determining parasite response to a variety of antimalarials in vitro and in vivo. In addition, P. falciparum ATPase 6 (PfATP6), a putative drug target of the widely used artemisinins, was also examined for possible drug-modulating mutations. First a real-time peR technique to measure amplification of pfmdri was developed and validated. This technique was used to determine pfmdri copy number in a unique set of field sample set (n = 600) collected in Northern Thailand, an area harbouring the world's most drug-resistant parasites. This allowed a comprehensive analysis of the importance of pfmdri amplification in (1) in vitro resistance to drugs, (2) in vivo response to mefloquine or mefloquine- artesunate therapy, (3) evolution of amplification in pre- and post-treatment samples. Subsequent studies also investigated the prevalence of pfmdrt amplification in Gabon, a Sub-Saharan country with very little mefloquine resistance. In addition, P. falciparum field isolates were studied for possible polymorphisms in PfATP6 and plasmid constructs generated to study the role of single nucleotide point mutations in the putative active site of the enzyme.
Supervisor: Not available Sponsor: Not available
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID:  DOI: Not available