The Plastid-Like Organelle of Apicomplexan Parasites as Drug Target

Wiesner, Jochen; Reichenberg, Armin; Heinrich, Stephanie; Schlitzer, Martin; Jomaa, Hassan

doi:10.2174/138161208784041105

Cited by 82 publications

(56 citation statements)

References 136 publications

(176 reference statements)

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“…Their 5-carbon precursors, IPP and DMAPP, are produced by the apicoplast (26,27). The synthesis of these precursors is the most important function of this organelle (11).…”

Section: Discussionmentioning

confidence: 99%

Synergistic Activity between Statins and Bisphosphonates against Acute Experimental Toxoplasmosis

Szajnman

et al. 2017

Antimicrob Agents Chemother

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Bisphosphonates are widely used for the treatment of bone disorders. These drugs also inhibit the growth of a variety of protozoan parasites, such as Toxoplasma gondii, the etiologic agent of toxoplasmosis. The target of the most potent bisphosphonates is the isoprenoid biosynthesis pathway enzyme farnesyl diphosphate synthase (FPPS). Based on our previous work on the inhibitory effect of sulfurcontaining linear bisphosphonates against T. gondii, we investigated the potential synergistic interaction between one of these derivatives, 1-[(n-heptylthio)ethyl]-1,1-bisphosphonate (C7S), and statins, which are potent inhibitors of the host 3-hydroxy-3-methyl glutaryl-coenzyme A reductase (3-HMG-CoA reductase). C7S showed high activity against the T. gondii bifunctional farnesyl diphosphate (FPP)/geranylgeranyl diphosphate (GGPP) synthase (TgFPPS), which catalyzes the formation of FPP and GGPP (50% inhibitory concentration [IC 50 ] ϭ 31 Ϯ 0.01 nM [mean Ϯ standard deviation]), and modest effect against the human FPPS (IC 50 ϭ 1.3 Ϯ 0.5 M). We tested combinations of C7S with statins against the in vitro replication of T. gondii. We also treated mice infected with a lethal dose of T. gondii with similar combinations. We found strong synergistic activities when using low doses of C7S, which were stronger in vivo than when tested in vitro. We also investigated the synergism of several commercially available bisphosphonates with statins both in vitro and in vivo. Our results provide evidence that it is possible to develop drug combinations that act synergistically by inhibiting host and parasite enzymes in vitro and in vivo.

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“…Their 5-carbon precursors, IPP and DMAPP, are produced by the apicoplast (26,27). The synthesis of these precursors is the most important function of this organelle (11).…”

Section: Discussionmentioning

confidence: 99%

Synergistic Activity between Statins and Bisphosphonates against Acute Experimental Toxoplasmosis

Szajnman

et al. 2017

Antimicrob Agents Chemother

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“…(the causative agents of malaria) and Toxoplasma spp. (33). The recent completion of the genome sequencing projects for two Theileria species, T. parva (11) and T. annulata (causative agent of tropical theileriosis) (24), now makes it possible to bioinformatically survey this important genus for promising apicoplast drug targets.…”

mentioning

confidence: 99%

Theileria Apicoplast as a Target for Chemotherapy

Lizundia

Werling

Langsley

et al. 2009

Antimicrob Agents Chemother

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“…It is interesting to note that Plasmodium species possess a plastid called apicoplast, derived from a secondary endosymbiosis involving a red alga ancestor (for review, see refs. [70][71][72]. Some genes contained in the original alga have been translocated to the nuclear genome of the parasite and we assume that the PMT gene was acquired following such horizontal transfer.…”

Section: Etn Incorporationmentioning

confidence: 99%

Rodent and nonrodent malaria parasites differ in their phospholipid metabolic pathways

Déchamps

Maynadier

Wein

et al. 2010

Journal of Lipid Research

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Malaria is a disease caused by an intraerythrocytic protozoan parasite of the genus Plasmodium , which is transmitted by dipterans and affects vertebrates such as reptiles, birds, and mammals, including humans (see supplementary Table I). By contrast with other Apicomplexa parasite species that can infect a broad range of metazoans, Plasmodium species have a narrow specifi city range regarding insect and vertebrate hosts ( 1 ). Plasmodium falciparum is, thus, responsible for the most severe form of malaria in humans only. Other species, such as P. vivax , two P. ovale subspecies ( 2 ), P. malariae , and, according to recent reports, P. knowlesi ( 3 ) cause less complicated forms of human malaria. The host specifi city of P. knowlesi is not restricted to humans because it also infects monkeys.The evolutionary history of Plasmodium species has been highly debated, especially the position of P. falciparum , either grouped with avian parasites ( 4, 5 ) or placed as a sister species to other mammalian parasites including rodent parasites. The fi ndings of most recent analyses using three classes of rare genomic changes and mitochondrial RNA genes unambiguously support a mammalian clade and no Abstract Malaria, a disease affecting humans and other animals, is caused by a protist of the genus Plasmodium . At the intraerythrocytic stage, the parasite synthesizes a high amount of phospholipids through a bewildering number of pathways. In the human Plasmodium falciparum species, a plant-like pathway that relies on serine decarboxylase and phosphoethanolamine N-methyltransferase activities diverts host serine to provide additional phosphatidylcholine and phosphatidylethanolamine to the parasite. This feature of parasitic dependence toward its host was investigated in other Plasmodium species. In silico analyses led to the identifi cation of phosphoethanolamine N-methyltransferase gene orthologs in primate and bird parasite genomes. However, the gene was not detected in the rodent P. berghei , P. yoelii , and P. chabaudi species. Biochemical experiments with labeled choline, ethanolamine, and serine showed marked differences in biosynthetic pathways when comparing rodent P. berghei and P. vinckei , and human P. falciparum species. Notably, in both rodent parasites, ethanolamine and serine were not signifi cantly incorporated into phosphatidylcholine, indicating the absence of phosphoethanolamine N-methyltransferase activity. To our knowledge, this is the fi rst study to highlight a crucial difference in phospholipid metabolism between Plasmodium species. The fi ndings should facilitate efforts to develop more rational approaches to identify and evaluate new targets for antimalarial therapy.

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The Plastid-Like Organelle of Apicomplexan Parasites as Drug Target

Cited by 82 publications

References 136 publications

Synergistic Activity between Statins and Bisphosphonates against Acute Experimental Toxoplasmosis

Synergistic Activity between Statins and Bisphosphonates against Acute Experimental Toxoplasmosis

Theileria Apicoplast as a Target for Chemotherapy

Rodent and nonrodent malaria parasites differ in their phospholipid metabolic pathways

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