Targeting Protein Translation in Organelles of the Apicomplexa

doi:10.1016/j.pt.2016.09.011

Trends in Parasitology

Volume 32, Issue 12, December 2016, Pages 953-965

https://doi.org/10.1016/j.pt.2016.09.011 Get rights and content

Trends

Recent molecular and chemical rescue studies confirm that the apicoplast is the primary target for several antiparasitic drugs targeting organellar protein synthesis.

Many new compounds inhibiting organellar protein synthesis in apicomplexans have recently been developed, but few appear to be superior to antibiotics in current use. Nonetheless, several additional compounds may be suitable as replacements if resistance to existing antibiotics becomes a major problem.

Antiparasitic compounds that inhibit organellar ribosomes are numerous and are widely studied. tRNA synthetases are emerging as a second category of targets for diverse and potent chemical classes with activity against multiple parasite life stages. Selectivity and safety issues remain to be addressed for the most active of these.

Antibiotics inhibiting protein translation have long been used to treat and prevent infections by apicomplexan parasites. These compounds kill parasites by inhibiting organellar translation, and most act specifically against the apicoplast, a relict plastid in apicomplexans. Drug resistance in Plasmodium and other apicomplexans dictates a need for development of novel targets. Some apicoplast inhibitors have a delayed onset of action, so they cannot replace fast-acting drugs, although they still fulfil important roles in treating and preventing infections. The plethora of bacterial-like actors in the translation machinery of parasite mitochondria and plastids presents validated targets with strong potential for selectivity. Here we discuss existing drugs that inhibit organellar translation, and explore targets that may be further exploited in antiparasitic drug design.

Section snippets

Targeting Protein Translation: From Bacteria to the Apicomplexa

Compounds that block protein translation stand out as the most diverse and successful class of anti-infective drugs. Their importance is demonstrated by their widespread representation in the natural antimicrobial arsenal of microorganisms and, not coincidently, by their extensive adoption by humans for use in treating infections. Ancient divergences of bacterial and eukaryotic translation machines provide abundant molecular differences that allow selective chemical inhibition of bacterial

Translation Inhibitors and Delayed Death

A hallmark of inhibitors of apicoplast translation (and inhibitors of some other apicoplast housekeeping enzymes, particularly fluoroquinolone inhibitors of DNA gyrases) is their delayed lethal action against parasites, known as the ‘delayed death’ effect (Figure 1). Parasites treated with delayed death drugs continue to grow, segment, egress, and invade a new host cell before arresting in this second infection cycle, even if the drug is washed away prior to invasion of a new host cell. When

The Organellar Ribosome As a Drug Target

Apicoplast ribosomes are the target for the majority of drugs inhibiting translation in apicomplexans. Three such ribosome-inhibiting antibacterial classes – the tetracyclines, lincosamides, and macrolides – are approved for use in the treatment of many of the diseases caused by apicomplexan parasites, including malaria, toxoplasmosis, theileriosis, and babesiosis 20, 21, 25, 26. However, despite the extensive examination of ribosomal-targeting drugs as inhibitors of apicomplexan parasites,

Inhibitors of Aminoacyl tRNA Synthetases

A key class of drug targets central to organellar protein translation is the aminoacyl-tRNA synthetase family (aaRS). These enzymes provide substrates for protein translation through the aminoacylation reaction, which involves the ATP-dependent attachment of a tRNA molecule to its cognate amino acid. A separate aaRS is required for each amino acid, and some aaRSs also contain proofreading and editing domains. These properties of aaRSs are key to translational fidelity. Gene transfer after

Potential Organellar Translation Inhibitors without Delayed Death

Although the vast majority of inhibitors of organellar protein translation target either the ribosomes or tRNA synthetases, several other aspects of organellar translation present targets for inhibitors. One such family of targets are the elongation factors. Prokaryotic elongation factors (reviewed in this issue by Habib and colleagues [68]) are proteins required for the continuation of polypeptide elongation after translation has initiated. Elongation factor EF-Tu is a GTPase that is

Translation in Apicomplexan Mitochondria

Given the wealth of data on apicoplast translation and its inhibition, we know surprisingly little about mitochondrial inhibitors. Although antibiotics were originally thought to kill apicomplexan parasites through mitochondrial inhibition 3, 4, many of these have subsequently been revealed to have apicoplast targets.

The ability of IPP to entirely rescue Plasmodium from translation inhibitors such as doxycycline [17] and indolmycin [57] shows that inhibition of mitochondrial translation by

Translation Inhibition beyond the Blood Stage

In comparison to their effects on disease-causing stages, relatively little is known about the effects of translation inhibitors on the mosquito and liver stages of parasite development. Azithromycin and doxycycline taken up in the blood meal appear to have only a modest impact on the infection of the mosquito by malaria parasites 86, 87, 88. Additionally, these drugs can perturb the mosquito microbiota [86], which is an important component of the mosquito's defense against parasite infection

The Clinical and Veterinary Use of Organellar Translation Inhibitors in Apicomplexans

A remarkably wide range of translation-inhibiting drugs is known to kill a diverse array of parasites from apicoplast-bearing apicomplexan genera. Prokaryotic protein translation inhibitors kill or inhibit growth of in vitro-cultured Toxoplasma gondii tachyzoites 13, 91, Neospora caninum tachyzoites [92], Plasmodium trophozoites (reviewed in [39]), Theileria parva sporozoites [93], and trophozoites from several Babesia species [94]. In whole-animal models of infection, Eimeria has also been

Concluding Remarks

Translation inhibitors are proven success stories as drugs that prevent and treat apicomplexan infections. Although there are some indications of emergence of isolated resistance and treatment failure for some of these antibiotics, they remain largely effective and relatively safe drugs for many antiparasitic applications. There is some argument for wider use of additional existing antibiotics, particularly in cases where other existing drugs are failing or inadequate [102]. In addition, a

Glossary

Aminoacyl tRNA synthetase (aaRS): an enzyme that uses energy from the hydrolysis of ATP to charge a tRNA with its corresponding amino acid. Once a tRNA is charged, its amino acid can be transferred to a growing peptide chain by the ribosome.
Antibiotics: drugs that kill, or inhibit the growth of, bacteria and are primarily used to treat or prevent bacterial infections. Also called antibacterials.
Apicomplexa: a phylum of single-celled eukaryotes which are primarily obligate intracellular parasites.

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New insights into apicoplast metabolism in blood-stage malaria parasites
2023, Current Opinion in Microbiology
Citation Excerpt :
Overall, the MEP pathway is a validated drug target for malaria parasites and significant effort has been put into inhibitor discovery in recent years [36–45]. A variety of antibacterial drugs (such as azithromycin, clindamycin, and doxycycline) kill blood-stage malaria parasites by inhibiting the prokaryotic ribosomes found in the apicoplast [46,47]. A key insight into apicoplast metabolism came from the observation that the isoprenoid precursor IPP can bypass the toxic effects of these antibacterial drugs [23].
The apicoplast of Plasmodium falciparum is the only source of essential isoprenoid precursors and Coenzyme A (CoA) in the parasite. Isoprenoid precursor synthesis relies on the iron–sulfur cluster (FeS) cofactors produced within the apicoplast, rendering FeS synthesis an essential function of this organelle. Recent reports provide important insights into the roles of FeS cofactors and the use of isoprenoid precursors and CoA both inside and outside the apicoplast. Here, we review the recent insights into the roles of these metabolites in blood-stage malaria parasites and discuss new questions that have been raised in light of these discoveries.
Control of human toxoplasmosis
2021, International Journal for Parasitology
Citation Excerpt :
The endosymbiotic origin of the apicoplast of T. gondii means that this compartment houses a bacterially-derived translational machinery (e.g., 70S ribosomes). Numerous inhibitors of bacterial translation have been shown to inhibit the proliferation of T. gondii (Fig. 1) and other apicomplexans (Goodman et al., 2016); for example, clindamycin, an inhibitor of the bacterial 50S (large) ribosomal subunit, inhibits T. gondii proliferation (Pfefferkorn et al., 1992) and has been used in clinical treatment of toxoplasmic encephalitis patients in combination with pyrimethamine (Dannemann et al., 1992). Clindamycin-resistant T. gondii strains have mutations in the large rRNA that is encoded on the apicoplast genome (Camps et al., 2002), suggesting that clindamycin targets protein translation in the apicoplast of these parasites.
Toxoplasmosis is caused by Toxoplasma gondii, an apicomplexan parasite that is able to infect any nucleated cell in any warm-blooded animal. Toxoplasma gondii infects around 2 billion people and, whilst only a small percentage of infected people will suffer serious disease, the prevalence of the parasite makes it one of the most damaging zoonotic diseases in the world. Toxoplasmosis is a disease with multiple manifestations: it can cause a fatal encephalitis in immunosuppressed people; if first contracted during pregnancy, it can cause miscarriage or congenital defects in the neonate; and it can cause serious ocular disease, even in immunocompetent people. The disease has a complex epidemiology, being transmitted by ingestion of oocysts that are shed in the faeces of definitive feline hosts and contaminate water, soil and crops, or by consumption of intracellular cysts in undercooked meat from intermediate hosts. In this review we examine current and future approaches to control toxoplasmosis, which encompass a variety of measures that target different components of the life cycle of T. gondii. These include: education programs about the parasite and avoidance of contact with infectious stages; biosecurity and sanitation to ensure food and water safety; chemo- and immunotherapeutics to control active infections and disease; prophylactic options to prevent acquisition of infection by livestock and cyst formation in meat; and vaccines to prevent shedding of oocysts by definitive feline hosts.
Delayed Death by Plastid Inhibition in Apicomplexan Parasites
2019, Trends in Parasitology
The discovery of a plastid in apicomplexan parasites was hoped to be a watershed moment in the treatment of parasitic diseases as it revealed drug targets that are implicitly divergent from host molecular processes. Indeed, this organelle, known as the apicoplast, has since been a productive therapeutic target for pharmaceutical interventions against infections by Plasmodium, Toxoplasma, Babesia, and Theileria. However, some inhibitors of the apicoplast are restricted in their treatment utility because of their slow-kill kinetics, and this characteristic is called the delayed death effect. Here we review the recent genetic and pharmacological experiments that interrogate the causes of delayed death and explore the foundation of this phenomenon in Plasmodium and Toxoplasma parasites.
Drug targeting of one or more aminoacyl-tRNA synthetase in the malaria parasite Plasmodium falciparum
2018, Drug Discovery Today
Citation Excerpt :
Since 2009, encouragingly, several groups have been investigating the structure–function attributes of the malarial parasite aminoacyl-tRNA synthetase (aaRSs) family in P. falciparum [9–22]. Targeting parasite aaRSs can provide an additional drug component in the current multidrug antimalarial therapy [9–23]. A recent example of success in targeting aaRSs comes from tavaborole (Kerydin®) – an FDA-approved antifungal drug that works on the editing domain of leucyl-tRNA synthetase against onychomycosis [24,25].
Malaria remains a major infectious disease and, despite incidence reduction, it threatens resurgence in drug-resistant forms. Antimalarial drugs remain the mainstay of therapeutic options and hence there is a constant need to identify and validate new druggable targets. Plasmodium falciparum aminoacyl-tRNA synthetases (Pf-aaRSs) drive protein translation and are potent targets for development of next-generation antimalarials. Here, we detail advances made in structural-biology-based investigations in Pf-aaRSs and discuss their distribution of druggable pockets. This review establishes a platform for systematic experimental dissection of malarial parasite aaRSs as a new focus for sustained drug development efforts against malaria.
The mitochondrial ribosomal protein L13 is critical for the structural and functional integrity of the mitochondrion in Plasmodium falciparum
2018, Journal of Biological Chemistry
The phylum Apicomplexa contains a group of protozoa causing diseases in humans and livestock. Plasmodium spp., the causative agent of malaria, contains a mitochondrion that is very divergent from that of their hosts. The malarial mitochondrion is a clinically validated target for the antimalarial drug atovaquone, which specifically blocks the electron transfer activity of the bc₁ complex of the mitochondrial electron transport chain (mtETC). Most mtETC proteins are nuclear-encoded and imported from the cytosol, but three key protein subunits are encoded in the Plasmodium mitochondrial genome: cyt b, COXI, and COXIII. They are translated inside the mitochondrion by mitochondrial ribosomes (mitoribosomes). Here, we characterize the function of one large mitoribosomal protein in Plasmodium falciparum, PfmRPL13. We found that PfmRPL13 localizes to the parasite mitochondrion and is refractory to genetic knockout. Ablation of PfmRPL13 using a conditional knockdown system (TetR-DOZI-aptamer) caused a series of adverse events in the parasite, including mtETC deficiency, loss of mitochondrial membrane potential (Δψ_m), and death. The PfmRPL13 knockdown parasite also became hypersensitive to proguanil, a drug proposed to target an alternative process for maintaining Δψ_m. Surprisingly, transmission EM revealed that PfmRPL13 disruption also resulted in an unusually elongated and branched mitochondrion. The growth arrest of the knockdown parasite could be rescued with a second copy of PfmRPL13, but not by supplementation with decylubiquinone or addition of a yeast dihydroorotate dehydrogenase gene. In summary, we provide first and direct evidence that mitoribosomes are essential for malaria parasites to maintain the structural and functional integrity of the mitochondrion.
Lost in the Light: Plastid Genome Evolution in Nonphotosynthetic Algae
2018, Advances in Botanical Research
Citation Excerpt :
The cyanobacterial-derived pathways within the apicoplast “are all very distant from human host metabolism and cellular processes, leaving room to design or discover specific inhibitors that would perturb the apicoplast but have no side effects” (McFadden & Yeh, 2017). Scientists are desperately trying, and have had some moderate success, in designing drugs blocking key apicoplast pathways, including those connected to the replication, transcription, and translation of ptDNA (Goodman, Pasaje, Kennedy, McFadden, & Ralph, 2016). It's not just humans who are at the mercy of parasitic nonphotosynthetic algae: the apicoplast-containing genera Babesia, Eimeria, and Theileria can cause serious diseases in domesticated (and undomesticated) animals, such as cattle, chickens, and other livestock (Foth & McFadden, 2003).
Photosynthesis is an awe-inspiring process. It has shaped, coloured, and diversified the biological world in innumerable ways and supplies us with the air we breathe. Photosynthetic organisms are literally our lifelines on Earth. Without them we perish. Perhaps this is why many of us are uncomfortable with and confused by the concept of a photosynthetic organism forfeiting its ability to convert sunlight into chemical energy, giving up its life-sustaining powers. Indeed, the evolutionary loss of photosynthesis, which has occurred countless times throughout evolution, remains a poorly understood and underappreciated topic, both among researchers and the general public. This is unfortunate because nonphotosynthetic plants and algae represent some of the most diverse and interesting (and even deadly) species on the planet, and they can teach us a lot about photosynthesis and biology as a whole. Here, I review the origins and evolution of nonphotosynthetic eukaryotic algae. I portray these biologically “broken light bulbs” in a contemporary framework, paying particular attention to their plastid genomes, which are much more complex and architecturally varied than one might expect. If you are anything of a rebel and prefer misfits over conformists, trouble makers over the straight-laced, and mysteries over simple plotlines, then you will not be disappointed by the eclectic assemblage of algae that have relinquished their hold on the sun.

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Trends in Parasitology

ReviewTargeting Protein Translation in Organelles of the Apicomplexa

Trends

Section snippets

Targeting Protein Translation: From Bacteria to the Apicomplexa

Translation Inhibitors and Delayed Death

The Organellar Ribosome As a Drug Target

Inhibitors of Aminoacyl tRNA Synthetases

Potential Organellar Translation Inhibitors without Delayed Death

Translation in Apicomplexan Mitochondria

Translation Inhibition beyond the Blood Stage

The Clinical and Veterinary Use of Organellar Translation Inhibitors in Apicomplexans

Concluding Remarks

Glossary

Mol. Biochem. Parasitol.

Mol. Biochem. Parasitol.

Int. J. Parasitol.

J. Infect.

Ticks Tick Borne Dis.

Vet. Parasitol.

J. Biol. Chem.

Int. J. Antimicrob. Agents

J. Biol. Chem.

Mol. Biochem. Parasitol.

Int. J. Parasitol: Drugs Drug Resist.

Int. J. Parasitol.

J. Biol. Chem.

Structure

Cell Host Microbe

Protist

Int. J. Parasitol.

Lancet

Vet. Parasitol.

Mol. Biochem. Parasitol.

Mol. Biochem. Parasitol.

Arch. Biochem. Biophys.

Structure

FEBS Lett.

Vet. Parasitol.

The use of antibiotics in the treatment of malaria

Ann. N. Y. Acad. Sci.

Aureomycin in Theileria parva infection

Nature

Oxygen- and time-dependent effects of antibiotics and selected mitochondrial inhibitors on Plasmodium falciparum in culture

Antimicrob. Agents Chemother.

Plastid in human parasites

Nature

A plastid of probable green algal origin in apicomplexan parasites

Science

Complete gene map of the plastid-like DNA of the malaria parasite Plasmodium falciparum

J. Mol. Biol.

Tetracyclines specifically target the apicoplast of the malaria parasite Plasmodium falciparum

Antimicrob. Agents Chemother.

Multiple antibiotics exert delayed effects against the Plasmodium falciparum apicoplast

Antimicrob. Agents Chemother.

Effects of antibiotics on Plasmodium falciparum in vitro

Am. J. Trop. Med. Hyg.

Parasiticidal effect of clindamycin on Toxoplasma gondii grown in cultured cells and selection of a drug-resistant mutant

Antimicrob. Agents Chemother.

In vitro assays elucidate peculiar kinetics of clindamycin action against Toxoplasma gondii

Antimicrob. Agents Chemother.

A plastid organelle as a drug target in apicomplexan parasites

Nature

A plastid segregation defect in the protozoan parasite Toxoplasma gondii

EMBO J.

Chemical rescue of malaria parasites lacking an apicoplast defines organelle function in blood-stage Plasmodium falciparum

PLoS Biol.

A chemical rescue screen identifies a Plasmodium falciparum apicoplast inhibitor targeting MEP isoprenoid precursor biosynthesis

Antimicrob. Agents Chemother.

Antimalarial drug discovery – the path towards eradication

Parasitology

A systematic review and meta-analysis of the efficacy of anti-Toxoplasma gondii medicines in humans

PLoS One

Chemical attenuation of Plasmodium in the liver modulates severe malaria disease progression

J. Immunol.

Cross-species malaria immunity induced by chemically attenuated parasites

J. Clin. Invest.

Theileria apicoplast as a target for chemotherapy

Antimicrob. Agents Chemother.

Comparison of mutants of Toxoplasma gondii selected for resistance to azithromycin, spiramycin, or clindamycin

Review
Targeting Protein Translation in Organelles of the Apicomplexa