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Title: A study of the mechanism of action and resistance of artemisinin antimalarials in Plasmodium falciparum
Author: Phanchana, M.
ISNI:       0000 0004 6422 6500
Awarding Body: University of Liverpool
Current Institution: University of Liverpool
Date of Award: 2017
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Malaria remains a global health and economic issue affecting nearly half of the world's population. In the past decade, effective chemotherapy and vector control have been the major interventions used to control and reduce the burden of malaria. However, resistance to antimalarial drugs and insecticides is compromising the control and treatment strategies and the goal to eliminate malaria. In most malaria endemic countries, artemisinin combination therapies (ACTs) are the first line treatment for uncomplicated Plasmodium falciparum malaria, the most lethal cause of malaria. Despite the widespread use of artemisinin-based therapies, the mechanism of action of this class of drug remains elusive. Emergence of resistance to ACTs in South East Asia is a global concern for drug efficacy. In this thesis, a click chemistry coupled with mass spectrometry (MS) proteomics approach was used to identify the molecular targets of artemisinin in various stages of P. falciparum strain 3D7 and extensively applied to the candidate trioxolanes, a new class of fully-synthetic artemisinin-like drugs. Using artemisinin activity-based probes, a number of biological targets were identified, these targets derive from key biological pathways/process that include; haemoglobin metabolism, glycolysis, nucleic acid and protein biosynthesis, antioxidant defence and oxidative stress response. The identified fingerprint of biological targets was similar between semi synthetic artemisininin and fully synthetic next generation artemisinins. Identified biological targets were enriched with glutathionylated proteins, indicating that these proteins are vulnerable to endoperoxide antimalarial inhibition and loss of function. The shared protein targets or protein pattern of semisynthetic artemisinin and fully synthetic trioxolane suggest that they might share similar mechanism or action and, possibly, mechanism of resistance. This raises the concern of cross resistance between them. The ring stage parasites which showed the least sensitivity to artemisinins and associated with resistance to artemisinins have much less proteins identified, including the absence of proteins in haemoglobin metabolism and reduction in proteins of major pathways. These findings support the working hypothesis that artemisinin is most effective against later stages of the parasite in line with the activity of haemoglobin digestion, the main activator of artemisinins and other endoperoxides. The reduced sensitivity during the ring stage is possibly due to less activation of artemisinin. A whole genome sequence comparative approach was undertaken with parasites displaying phenotypic artemisinin resistance (slow clearance phenotype) derived from an experimental in vivo model of infection. Parasite genes that we correlated to the slow clearance phenotype included genes involved in the unfolded protein response pathway consistent with recent models of parasite resistance to artemisinins. The results presented in this thesis using chemical biology and omics technologies, have contributed to our understanding of the mechanism of action and resistance of endoperoxides and offer future research directions to study this important class of antimalarials.
Supervisor: Ward, S. A. ; Biagini, G. A. Sponsor: Not available
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral