Isoprenoid precursor transport as fosmidomycin recrudescence factor in intraeritrocytic stages of Plasmodium falciparum

• Grant number: 18/02924-9
• Support type: Scholarships in Brazil - Post-Doctorate
• Effective date (Start): October 01, 2018
• Status: Discontinued
• Field of knowledge: Biological Sciences - Biochemistry - Biochemistry of Microorganisms
• Principal researcher: Alejandro Miguel Katzin
• Grantee: Marcell Crispim
• Home Institution: Instituto de Ciências Biomédicas (ICB). Universidade de São Paulo (USP). São Paulo , SP, Brazil
• Associated research grant: 17/22452-1 - Biosynthesis of isoprenoids in Plasmodium falciparum: evaluation of possible targets to obtain new anti-malarial drugs, AP.TEM
• Associated scholarship(s): 20/14897-6 - Phytol distribution in malaria parasites, BE.EP.PD

Abstract

The isoprenoid biosynthesis has been studied in Apicomplexa pathogens due to its particularity: these organisms present the typical route of photosynthetic or bacterial organisms, the methyl erythritol-phosphate pathway (MEP; DOXP). This fact encouraged numerous research groups to: (i) a fine characterization of the MEP enzymes and metabolites (i) study the role these enzymatic steps in parasitic biology (iii) the subsequent search for effective inhibitors of MEP, with antiplasmodial effect. All this progress culminated in the establishment of the MEP inhibitor fosmidomycin (Fos) and analogues as a promising therapy for malaria, also reaching to trials in humans with high rate of apparent initial cure. Unfortunately, the treatment with Fos has proved to be inefficient in the long term, with the resurgence of parasitemia and clinical manifestations, unleashing a recrudescence event. One of the hypotheses for this event is that the natural characteristics of P. falciparum, not yet investigated, could influence their sensitivity to Fos. Interestingly, it is usual the extracellular supply of radioactive isoprene precursors in metabolic labeling experiments for prenylated molecules investigation, and it is known that the isoprenoid precursor IPP (isopentenyl pyrophosphate) is able to reverse the Fos effect in vitro, raising doubts about the exclusivity of MEP as a isoprene units supplier for the parasite. In this context we decided to study the mechanism by which P. falciparum transports isoprene precursors from the extracellular environment, to investigate the biological role of this process and to evaluate the possible relationships with the parasite's ability to overcome Fos therapy.