Toxoplasma
Dongyou Liu in Handbook of Foodborne Diseases, 2018
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
An Overview of Parasite Diversity
Eric S. Loker, Bruce V. Hofkin in Parasitology, 2023
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.
Doxycycline
M. Lindsay Grayson, Sara E. Cosgrove, Suzanne M. Crowe, M. Lindsay Grayson, William Hope, James S. McCarthy, John Mills, Johan W. Mouton, David L. Paterson in Kucers’ The Use of Antibiotics, 2017
Tetracyclines, including doxycycline, inhibit bacterial protein synthesis through reversible binding to the ribosomal complex, preventing the association of aminoacyl-tRNA molecules with the bacterial ribosome and interfering with protein synthesis. Access to Gram-negative bacterial ribosomal binding targets on the 30S subunit is through porins, and via an energy-dependent process. Additional inhibition of protein synthesis occurs in mitochondria through binding of the doxycycline molecule to the 70S ribosomes. While some doxycycline-susceptible parasites have mitochondria that are inhibited by this drug, these are not the only parasitic targets. Apicoplast ribosomal subunits in P. falciparum appear to be inhibited by doxycycline (Dahl et al., 2006). Doxycycline inhibition of protein synthesis in these organelles prevents their replication, which results in an antiparasitic effect in daughter parasites that lack these organelles, thus explaining the slow antimalarial effect of doxycycline (Batty et al., 2007). The apicoplast houses enzymes involved in fatty acid synthesis and heme biosynthesis pathways.
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].
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.
Related Knowledge Centers
- Cryptosporidium
- Fatty Acid Synthesis
- Heme
- Photosynthesis
- Plasmodium Falciparum
- Plastid
- Terpenoid
- Toxoplasma Gondii
- Apomorphy & Synapomorphy
- Symbiogenesis