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An Overview of Parasite Diversity
Published in Eric S. Loker, Bruce V. Hofkin, Parasitology, 2023
Eric S. Loker, Bruce V. Hofkin
Although genes involved in photosynthesis have been deleted from the original plastid chromosome and apicomplexans are not capable of photosynthesis, the apicoplast does retain functional genes. If the apicoplast is disabled, the apicomplexan may be killed or be unable to penetrate new host cells. The apicoplast is an appealing target for the development of new drugs that would selectively target apicomplexans and leave the host (lacking plastid genomes) unaffected (see Chapter 9). The newly-discovered corallicolids, which are symbionts in the gastric cells of corals, are unique among known apicomplexans in retaining a few genes involved in chlorophyll synthesis in their apicoplast. They represent an interesting intermediate step along the path beginning with a photosynthetic ancestor to the parasitic lifestyle of present-day apicomplexans.
Toxoplasma
Published in Dongyou Liu, Handbook of Foodborne Diseases, 2018
Fernanda Silva de Souza, Renato Augusto DaMatta
T. gondii has two organelles with endosymbiotic origin: mitochondrion and apicoplast. Mitochondrion is a single and ramified organelle located in the periphery of the parasite42,43 with bulbous cristae.38,42 It has been recently demonstrated that the location of the mitochondrion changes from the periphery in intracellular tachyzoites to their interior when they are extracellularly located, indicating a mechanism that attaches this organelle to the pellicle when the parasite is in the host cells.44 The apicoplast is the apicomplexan plastids.38,45 It is an ovoid organelle found in the mid-region of the parasite, anterior to the nucleus, close to the Golgi complex, presenting four membrane units and internal ribosomes.14,38,45,46 It is a pigment-free vestigial plastid that does not photosynthesize but is essential, due to the metabolic capacity to generate fatty acids.45 The metabolic pathways are distant from human metabolism and, thus, are considered good drug targets.45–47
Treatment and prevention of malaria
Published in David A Warrell, Herbert M Gilles, Essential Malariology, 2017
David A Warrell, William M Watkins, Peter A Winstanley
This semisynthetic lincosamide antibiotic was derived from lincomycin by halogenation in the 7-position, to which is attributed its antimalarial activity. In bacteria, it acts by binding to the 50S subunit of the bacterial ribosome, as with macrolides, inhibiting the early stage of protein synthesis. In parasites of the phylum Apicomplexa, including Plasmodium, Toxoplasma and Eimeria, clindamycin may inhibit protein synthesis in a plastid organelle (apicoplast). Clindamycin has a slow-action blood schizontocidal activity against P. falciparum, including isolates resistant to 4-aminoquinolines and dihydrofolate reductase (DHFR) inhibitors, but it should never be used alone. In sequence with quinine and possibly chloroquine, it has proved effective against multiresistant P. falciparum in South America, Africa and South-east Asia. This combination is particularly useful in pregnant women and young children, in whom quinine-tetracycline combinations are contraindicated. Unfortunately, clindamycin is too expensive for most developing countries.
Toxoplasma gondii infection: novel emerging therapeutic targets
Published in Expert Opinion on Therapeutic Targets, 2023
Joachim Müller, Andrew Hemphill
The apicoplast, a specific organelle that is a plant chloroplast homolog, is found in T. gondii and other apicomplexans. Since these plastids harbor specific metabolic pathways absent from mammalian cells, it is natural that not only plastid-borne protein biosynthesis (see above) but also metabolic pathways are regarded as suitable anti-Toxoplasma drug targets [75,100]. Since lipid biosynthesis in plants is plastid-borne and can be targeted by various herbicides, it is straightforward to test such compounds against T. gondii. In vitro tachyzoite proliferation and activity of recombinant Acetyl-Coenzyme A-carboxylase, the first key enzyme of lipid biosynthesis, is inhibited by aryloxyphenoxypropionate herbicides [101]. Moreover, fatty acid synthase II is inhibited by the herbicide haloxyfop [102]. These studies and the generation of a conditional null mutant of the apicoplast acyl carrier protein reveal that apicoplast borne fatty acid biosynthesis is essential for the survival of T. gondii in vitro as well as in vivo [103]. In detail, apicoplast fatty acid synthesis seems to be essential to compounds required for the final step of parasite division [104].
Can Plasmodium’s tricks for enhancing its transmission be turned against the parasite? New hopes for vector control
Published in Pathogens and Global Health, 2019
S. Noushin Emami, Melika Hajkazemian, Raimondas Mozūraitis
Isoprenoids are widespread molecules and are necessary for all living organisms [58]. These molecules are involved in a vast spectrum of metabolic processes and serve as building blocks in the synthesis of various compounds such as cholesterol, steroid hormones and vitamins [59]. Animals, fungi and a few bacteria produce isoprenoids through a biosynthetic route called mevalonate pathway. By contrast, eubacteria, plastid-containing eukaryotes and most bacteria use an alternate metabolic route, the non-mevalonate or methylerythritol phosphate (MEP) pathway. Plants use both pathways, the chloroplast-localized MEP pathway that is used for biosynthesis of the terpene volatiles that contributs their characteristic flavors and fragrances [60]. MEP pathway is used by parasitic apicomplaxan protozoa, including Plasmodium (reviewed in [61]). The MEP pathway is one of the recognizable pathways in malaria parasite apicoplast and this pathway might have evolved due to its lower energy consumption (reviewed in [45]). Due to its non-host specificity, biochemical reactions of MEP pathway have been favored as a highlighted target for novel antiparasitic drugs in human host. For example, fosmidomycin and its derivative, FR-900098 have an antibiotic activity that targets DOXP reductoisomerase and inhibits the growth of asexual stage of malaria parasite [62]. Parasites lost their apicoplast after non-antifolate antibiotic treatments such as doxycycline. Interestingly, parasite growth (asexual stage) is rescued upon simultaneous supplementation with the central isoprenoid precursor, isopentenyl pyrophosphate (IPP) [63].
Discovery of small molecule inhibitors of Plasmodium falciparum apicoplast DNA polymerase
Published in Journal of Enzyme Inhibition and Medicinal Chemistry, 2022
Supreet Kaur, Nicholas S. Nieto, Peter McDonald, Josh R. Beck, Richard B. Honzatko, Anuradha Roy, Scott W. Nelson
Resistance to current Malaria drugs is inevitable and new drugs that target novel aspects of P. falciparum’s biology are necessary to combat the disease. The apicoplast is a validated drug target and inhibition of apicoplast DNA replication leads to the loss of the organelle and parasite death34. The large-scale high-throughput screen described here defined several sets of compounds that could serve as tools to investigate mechanisms of DNA polymerase inhibition or as lead compounds for further optimisation into anti-malaria drugs. Future work will involve determining mechanisms of inhibition, apPOL binding sites, and target(s) confirmation.