Identifying a Potential Drug-Drug Interaction Between Two Antimalarials and Understanding the Influence of Lipid Supplement Composition on Plasmodium falciparum
Open Access
- Author:
- Luck, Cuyler
- Millennium Scholars Program:
- Microbiology (MICRB)
- Degree:
- Bachelor of Science
- Document Type:
- Thesis
- Thesis Supervisor:
- Manuel Llinas, Thesis Supervisor
Ming Tien, Honors Advisor - Keywords:
- malaria
plasmodium falciparum
lipid supplement
albumax
serum
sj733
p218
combination therapy
isobologram - Abstract:
- Malaria remains a deadly and devastating disease across the globe, with Plasmodium falciparum responsible for the majority of cases and deaths. While antimalarials are currently still generally effective, resistance has arisen to all current classes of antimalarials and will spread in the future. To delay resistance in future treatments, combination therapies composed of synergistic drugs targeting different aspects of the parasite’s metabolism are desirable, while antagonistic combinations should be avoided. Here I tested for drug-drug interactions between (+)-SJ733 and P218, two candidate antimalarials, using a SYBR Green based fixed-ratio assay. The two drugs appear to act antagonistically, suggesting that they likely would not be an effective combination therapy despite presumably acting on different metabolic pathways. However, this should be confirmed with more optimal plate designs and curve fits as well as with comparisons to known pairs of antagonistic/synergistic antimalarials. Also explored is the impact that different lipid supplements have on P. falciparum in vitro. Human serum is often used as a lipid supplement for in vitro culture but is costly and variable between individuals, and different batches generate parasites which are differentially able to transmit to mosquitoes. Albumax, an artificial supplement, is standardized and cheaper, but cannot generate any transmissible gametocytes. Furthermore, several phenotypic changes in vitro have been shown in asexual parasites that are cultured in serum, Albumax, or a combination thereof. Metabolomics is being used to understand what metabolic differences exist between those supplements able to generate transmissible gametocytes and those that are not, and between parasites grown in Albumax versus serum.