Natural Products as a Source to Discover Novel Drug Targets in P. falciparum

Malaria is a deadly infectious disease that caused an estimated 216 million cases around the world in 2016 according to the World Health Organization. Plasmodium falciparum is the parasite responsible for causing the majority of malaria cases in humans. Resistance to all current frontline antimalarial therapies is a growing problem thus, there is an urgent need for new antimalarial drugs with novel targets. Natural products have a lengthy history of utility in drug discovery and remains a great source of new therapeutics. We have screened against P. falciparum in vitro cultures over 230 natural compounds isolated from various plants indigenous to the southern parts of China which have long been used in traditional Chinese medicine to treat malaria. This collection presented different degrees of antimalarial activity and toxicity toward mammalian cells. Two sesquiterpenoid dimers that exhibited potent antiplasmodial activities (<100 nM) and low toxicity to mammalian cells were selected to study their mechanism of action in more detail by inducing drug resistance in in vitro culture of P. falciparum . We were able to obtain resistant parasites against one of the selected sesquiterpenoid dimers. Clonal subcultures were subjected to next generation Illumina sequencing to identify the potential mechanism of resistance that may lead to the identification of the molecular target. In addition, a subset of similar sesquiterpenoid dimers present in this collection of natural products were screened against the resistant parasites and the analysis has outlined a starting point for structure‐activity relationship studies. We have identified a new class of promising antiplasmodial compounds due to their unique scaffold that is different from all currently known antimalarials and is likely acting through a new mechanism of action. This abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal .