dc.contributor.advisor |
Birkholtz, Lyn-Marie |
|
dc.contributor.coadvisor |
Louw, Abraham Izak |
|
dc.contributor.postgraduate |
Snyman, Janette |
|
dc.date.accessioned |
2013-09-09T12:11:54Z |
|
dc.date.available |
2012-05-21 |
en |
dc.date.available |
2013-09-09T12:11:54Z |
|
dc.date.created |
2012-04-19 |
en |
dc.date.issued |
2011 |
en |
dc.date.submitted |
2012-02-13 |
en |
dc.description |
Dissertation (MSc)--University of Pretoria, 2011. |
en |
dc.description.abstract |
The Apicomplexan parasite, P. falciparum, is one of the causative agents of the
morbidity and mortality in sub-Saharan Africa, especially children under 5 years of age
and pregnant women (1). The parasite harbours a non-photosynthetic plastid believed
to have been acquired from blue-green algae (2, 3). The presence of this apicoplast in
the parasite and its connection to plants opens many doors for to the development of
novel antimalarials not harmful to the human host.
In this study, a herbicide-derived compound (A51B1C1_1) with structural similarities to
1,2-diacylglycerol (DAG) was tested against P. falciparum. It was anticipated that this
herbicide would target similar pathways of the malaria parasite as was shown for
Arabidopsis. One such pathway is the synthesis of the glycerolipids.
Monogalactosyldiacylglycerol (MGDG) and digalactosyldiacylglycerol (DGDG) are the
two most studied galactolipids. MGDG is synthesised by MGDG synthase and DGDG
is synthesised by DGDG synthase from DAG.
Morphological studies after inhibition of P. falciparum parasites with A51B1C1_1
confirmed that the compound does have an effect on the parasites. The determined
IC50 value, the drug-like properties conforming to Lipinski’s rule of five and the
specificity of the compound towards the parasite makes A51B1C1_1 a possible
antimalarial compound. Transcriptomic data of A51B1C1_1 P. falciparum treated
parasites revealed 1504 differentially affected transcripts, of which 579 transcripts were
unique to this treatment. The differentially affected processes included apicoplastassociated
metabolic pathways such as glycerolipid and glycerophospholipid
metabolism. These results thus indicated that enzymes involved in glycerolipid
synthesis, especially those responsible for the metabolism of DAG, are affected in P.
falciparum parasites treated with A51B1C1_1.
Proteome analysis indicated that similar processes as shown for the transcriptomic data
were affected by the herbicide treatment. At the assay time-point, a total of 276
Plasmodial proteins were uniquely expressed in the A51B1C1_1 treated sample
whereas 204 Plasmodial proteins were uniquely expressed in the control sample.
Interestingly, the direction of the change in the abundance of these affected proteins did not necessarily correlate with the change of abundance observed in the transcriptomic
data, as seen numerous times before in other reported Plasmodial perturbations.
Global functional genomics aid in the confirmation that compound A51B1C1_1 does
affect glycerolipid and glycerophospholipid metabolism in P. falciparum as seen in
Arabidopsis after treatment with the parent compound Galvestine-1. Overall, this study
demonstrated the importance of functional genomics in the investigation for potential
antimalarial compounds and contributed in the progress of A51B1C1_1 from an early hit
to an early lead in the antimalarial drug discovery pipeline. |
en |
dc.description.availability |
Unrestricted |
en |
dc.description.degree |
MSc |
|
dc.description.department |
Biochemistry |
en |
dc.identifier.citation |
Snyman, J 2011, The effect of herbicides as novel antimalarial drugs on the transcriptome and proteome of Plasmodium falciparum, MSc Dissertation, University of Pretoria, Pretoria, viewed yymmdd <http://hdl.handle.net/2263/31345> |
en |
dc.identifier.other |
C12/4/114/gm |
en |
dc.identifier.upetdurl |
http://upetd.up.ac.za/thesis/available/etd-02132012-153856/ |
en |
dc.identifier.uri |
http://hdl.handle.net/2263/31345 |
|
dc.language.iso |
en |
en |
dc.publisher |
University of Pretoria |
|
dc.rights |
© 2011, University of Pretoria. All rights reserved. The copyright in this work vests in the University of Pretoria. No part of this work may be reproduced or transmitted in any form or by any means, without the prior written permission of the University of Pretoria C12/4/114/ |
en |
dc.subject |
UCTD |
en |
dc.title |
The effect of herbicides as novel antimalarial drugs on the transcriptome and proteome of Plasmodium falciparum |
en |
dc.type |
Dissertation |
en |