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Phenotypic characterization of chloroquine resistance in Plasmodium spp. isolates

Wirjanata, Grennady (2017). Phenotypic characterization of chloroquine resistance in Plasmodium spp. isolates. Doctor of Philosophy Thesis, Charles Darwin University.

Document type: Thesis
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Author Wirjanata, Grennady
Title Phenotypic characterization of chloroquine resistance in Plasmodium spp. isolates
Institution Charles Darwin University
Publication Date 2017-03
Thesis Type Doctor of Philosophy
Supervisor Marfurt, Jutta
Price, Ric N.
Noviyanti, Rintis
Abstract Malaria remains a major global health problem. Highly effective anti-malarial treatments are critical to the malaria elimination agenda. However, the emergence of multidrug-resistant P. falciparum and P. vivax challenge these efforts.
In this thesis, novel ex vivo tools were developed and applied to investigate various phenotypic aspects of anti-malarial resistance and resulted in the following principal findings:

1. Napththoquine and methylene blue showed potent ex vivo efficacy againstmultidrug resistant P. falciparum and P. vivax, highlighting their potential use for malaria treatment.

2. A rapid and robust drug susceptibility quantification method by using flowcytometry was developed; highlighting the potential use of this method forroutine ex vivo drug surveillance and higher throughput anti-malarial drugscreening.

3. The evaluation of various programs and online platforms to estimate anti-malarial IC50s, a key parameter in expressing cytostatic drug activity,provides useful guidance for researchers in making an informed decision onwhat analysis tool is most suitable for their purposes.

4. Testing of ‘reversed chloroquine’ compounds and CQ reversal agentsrevealed contrasting resistance reversal patterns between P. falciparum and P.vivax, indicating different CQ transport mechanism in the two species.

5. CQ transport kinetic studies using a novel field-applicable flow cytometryassay revealed contrasting patterns in P. falciparum and P. vivax, supportinga growing body of evidence suggesting different mechanisms of CQ actionand resistance in these two species.

This thesis contributed to the improvement of ex vivo tools for drug resistance surveillance and the screening of novel anti-malarial lead compounds. For the first time, the studies investigated CQ uptake and efflux in P. vivax and hence, contributed to a better understanding of the mechanisms of CQ action and resistance in this species. Finally, the phenotypic data provide a prerequisite for more in-depth genomic studies on the molecular determinants of anti-malarial resistance.

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