Malaria, the infectious disease caused by Plasmodium spp. remains a major problem worldwide due in part to treatment challenges such as increasing drug resistance and parasite recrudescence following treatment. This may be partially explained by dormancy, a mechanism that allows the parasite to escape stress such as that induced by current antimalarial treatments. Drug-induced dormancy involves the parasite entering a state of low metabolic activity, where infection may appear to have been cleared, but recrudescence occurs when parasites resume normal growth. Currently, the molecular basis for how the parasite is able to regulate dormancy and recrudescence is not well understood. We believe that abscisic acid (ABA), a carotenoid catabolite with a well established role in seed dormancy in plants, may answer some of these questions. ABA synthesis in Plasmodium requires the apicoplast, an organelle that was originally obtained via a secondary endosymbiotic relationship with red algae. The apicoplast serves as the site for isoprenoid biosynthesis, producing isopentyl pyrophosphate (IPP), which is essential for a number of metabolic processes and serves as the precursor for carotenoid biosynthesis. In this study, we discovered the presence of ABA in the erythrocytic stages of P. falciparum using gas chromatography mass spectroscopy (GC-MS) to detect and quantify ABA levels in methylated parasitic extracts exposed to different carotenoid inhibitors and apicoplast-targeting antibiotics. Our preliminary data detected ABA and found it to be significantly decreased when exposed to these drugs. Following in vitro induction of dormancy with dihydroartemesinin, parasites were observed to resume growth earlier when supplemented with ABA. We also found that fluridone (FLD), a potent inhibitor of ABA biosynthesis, causes growth delay in the normal parasite life cycle and extends the length of dormancy. We hypothesize that ABA acts as a stress sensor that helps regulate dormancy in P. falciparum. In this study, we aim to characterize the biosynthetic pathway of ABA using an innovative approach with 13C labeled precursors to follow incorporation into ABA and intermediates. We will also further elucidate the role that ABA has in drug induced dormancy using dihydroartemesinin and antifolate drugs. Our research strategy, which involves taking a novel approach by utilizing the evolutionary link between plants and parasites should help us broaden our understanding of parasite drug evasion and have an impact on development of antimalarials.
Many effective drugs exist to treat malaria but unfortunately the parasite has developed mechanisms to evade drug pressure, making treatment difficult. The aim of this project is to apply novel methods to characterize abscisic acid biosynthesis in Plasmodium falciparum and elucidate the role it plays in drug- induced dormancy of the asexual erythrocytic stages. Having a better understanding of this metabolite and establishing how it is utilized in the evasion mechanism of antimalarials will provide much needed insight that will help future malaria drug research.
| Duvalsaint, Marvin; Kyle, Dennis E (2018) Phytohormones, Isoprenoids, and Role of the Apicoplast in Recovery from Dihydroartemisinin-Induced Dormancy of Plasmodium falciparum. Antimicrob Agents Chemother 62: |
