More than 40% of the world's population is at risk of contracting malaria and drug resistance is a constant problem; thus, identification and characterization of new targets for development of antimalarial drugs with different modes of action is critically needed. Moreover, the activity of new drugs against gametocytes, the transmission stage of malaria, is recognized as a priority in the efforts to eradicate malaria. The isoprenoid biosynthetic pathway is a promising source of malaria-specific targets because: a) it occurs through the methylerythritol phosphate pathway in malaria parasites present in the apicoplast and is absent in humans; b) isoprenoid downstream products differ from those in the human host; and c) isoprenoids are involved in a wide variety of vital biological functions. Most of our knowledge about isoprenoid biosynthesis comes from studies performed in the asexual intraerythrocytic stages only. However, it is unknown: a) if isoprenoid biosynthesis occurs during gametocytogenesis, b) if the isoprenoid repertoire is similar to that present in the asexual stages and c) what the role of the isoprenoids are during gametocytogenesis. We hypothesize that isoprenoid biosynthesis is present in gametocyte stages and is essential for gametocytogenesis. In addition, we have identified a novel pathway for menaquinone biosynthesis, an isoprenoid product. Thus, the overarching goal of this application is to study isoprenoid biosynthesis in the malaria gametocyte stages and to characterize the menaquinone biosynthesis in the malaria parasites. To address these aims we will mainly use 13C-metabolic labeling in combination with state-of-the-art mass spectrometry analysis. Building on these studies, the long- term goal of this proposal is to identify novel targets and to validate known targets in gametocytes for future drug development to cure malaria and stop its transmission.
More than 40% of the world's population is at risk of contracting malaria and drug resistance is a constant problem; thus, identification and characterization of new targets for development of antimalarial drugs with different modes of action and active against gametocytes, the transmission stage, is critically needed. The overarching goal of this application is to study isoprenoid metabolism in the malaria gametocyte stages. Therefore, these studies will likely identify novel targets and validate known targets in gametocytes for future development of transmission-blocking drugs.
|Ghavami, Maryam; Merino, Emilio F; Yao, Zhong-Ke et al. (2018) Biological Studies and Target Engagement of the 2- C-Methyl-d-Erythritol 4-Phosphate Cytidylyltransferase (IspD)-Targeting Antimalarial Agent (1 R,3 S)-MMV008138 and Analogs. ACS Infect Dis 4:549-559|
|Barisón, María Julia; Rapado, Ludmila Nakamura; Merino, Emilio F et al. (2017) Metabolomic profiling reveals a finely tuned, starvation-induced metabolic switch in Trypanosoma cruzi epimastigotes. J Biol Chem 292:8964-8977|
|Saito, Alexandre Yukio; Sussmann, Rodrigo Antonio Ceschini; Kimura, Emilia Akemi et al. (2015) Quantification of nerolidol in mouse plasma using gas chromatography-mass spectrometry. J Pharm Biomed Anal 111:100-3|
|Yao, Zhong-Ke; Krai, Priscilla M; Merino, Emilio F et al. (2015) Determination of the active stereoisomer of the MEP pathway-targeting antimalarial agent MMV008138, and initial structure-activity studies. Bioorg Med Chem Lett 25:1515-9|
|Wiley, Jessica D; Merino, Emilio F; Krai, Priscilla M et al. (2015) Isoprenoid precursor biosynthesis is the essential metabolic role of the apicoplast during gametocytogenesis in Plasmodium falciparum. Eukaryot Cell 14:128-39|
|Laourdakis, Christian D; Merino, Emilio F; Neilson, Andrew P et al. (2014) Comprehensive quantitative analysis of purines and pyrimidines in the human malaria parasite using ion-pairing ultra-performance liquid chromatography-mass spectrometry. J Chromatogr B Analyt Technol Biomed Life Sci 967:127-33|