A Mechanism of Resistance and Mode of Action for Drugs Against Plasmodium falciparum

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  • March 19, 2019
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  • Purfield, Anne Elizabeth
    • Affiliation: School of Medicine, Department of Microbiology and Immunology
Abstract
  • The need for new drugs to control widespread malaria caused by Plasmodium falciparum is critical. Parasite resistance to currently used drugs is rampant and, in many cases, the drug's mode of action and/or mechanism of resistance is unknown. The three objectives of this dissertation address issues associated with resistance to the currently used antimalarial drugs, in addition to elucidating the mechanism of action of a novel antimalarial compound in development. First, a real time PCR method was developed to distinguish parasite genotypes associated with mefloquine resistance in vitro. Single nucleotide point mutations in the Plasmodium falciparum multi-drug resistance-1 (pfmdr1) gene are associated with mefloquine resistance in vitro. This method may be applied to clinical malaria samples and used to predict treatment outcome as well as for surveillance of drug resistance. In addition, the mechanism of action for the novel compound, [2,5-bis(4-amidinophenyl) furan], (DB75) was investigated. DB75, the active metabolite of the oral pro-drug DB289, is a broad spectrum antiparasitic agent with impressive antimalarial activity both in vitro and in vivo. It is currently in development for treatment of falciparum malaria, however the mode of action against falciparum parasites is unknown. Results from ultraviolet confocal microscopy showed DB75 localization exclusively in the nucleus of parasites in culture. Further, microscopy studies using blood smears to distinguish morphologies suggested DB75 has a life stage-specific mechanism. Parasites must be exposed during the ring stage for effective killing. Finally, real time PCR gene expression assays suggested high concentrations of DB75 may alter the expression pattern in a manner consistent with the delay in maturation. However, DB75 did not inhibit or enhance global nuclear transcription or developmental expression of six select genes. The third objective was to determine potential synergistic interactions of DB75 in combination with current antimalarial drugs to determine a mechanism of action for DB75 and to identify potential partner drugs for use in combination therapy with DB75. Taken together, this work contributes to the arsenal of tools for surveillance of falciparum malaria drug resistance and partially elucidates a mechanism of action for a novel antimalarial diamidine that may be used for malaria therapy.
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  • In Copyright
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  • Meshnick, Steven R.
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