Date of Award

January 2025

Document Type

Open Access Thesis

Degree Name

Master of Public Health (MPH)

Department

School of Public Health

First Advisor

Amy K. Bei

Abstract

Malaria is a deadly disease responsible for 263 million cases and 597,000 deaths in 2023, with the majority being from the WHO African Region. While resistance to chloroquine and sulfadoxine-pyrimethamine (SP) emerged decades ago, there have been records of partial resistance to artemisinin-based combination therapies (ACTs) in African countries like Rwanda, Uganda, and Ethiopia. Given that ACTs are the main malaria drug of choice in Africa, there is a need to develop novel antimalarial agents that target pathways not explored by the current antimalarial therapies. Mutations in coding genes (PfSec13 and Pfendoplasmin or PfEndo) have been previously associated with resistance to MED6-189 (a novel antimalarial drug candidate in the isocyanoterpene class). Given MED6-189’s complex mechanism of action and low median inhibitory concentration (IC50) of <50 nM, we sought to detect whether structural analogs of this compound retain antimalarial efficacy in the face of PfSec13, PfEndo, and partner drug mutations identified in P. falciparum isolates sourced from Senegal (Thiès and Kédougou). Amplification of the PfSec13 and PfEndo genes was done on 96 samples, which were then sequenced based on the Illumina sequencing technology. Results of preliminary in vitro phenotypic drug assays using a series of 10-fold dilutions revealed analog GB-79 to have IC50 values of <81 nM. In addition to detecting a novel single nucleotide polymorphism (SNP) (N685I) in the PfSec gene (with a high prevalence of 7.8%), we found that the majority of the mutations in the Thiès isolates were deletions having a tandem repeat sequence while Kédougou isolates had a high prevalence of previously detected SNPs from literature (S497G and G494E). The findings of this study elucidate the antimalarial potential of MED6-189’s analogs and the genetic diversity present in the PfSec13 and PfEndo genes, supporting continued research aimed at discovering novel antimalarial drug candidates.

Comments

This is an Open Access Thesis.

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