Delayed Death by Plastid Inhibition in Apicomplexan Parasites

Kennedy, Kit; Crisafulli, Emily M.; Ralph, Stuart A.

doi:10.1016/j.pt.2019.07.010

Cited by 41 publications

(34 citation statements)

References 100 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Inactivation of the apicoplast-located TgSufS had a marked effect on the organelle itself, as it led ultimately to a loss of the apicoplast, which is consistent with the phenotype observed when disrupting the Suf pathway in Plasmodium (31). Isoprenoid synthesis is vital for T. gondii tachyzoites (38), and it has implication beyond the apicoplast, as prenylated proteins or isoprenoid precursors are involved in more general cellular processes including intracellular trafficking or mitochondrial respiration (85). Impairing isoprenoid synthesis does not, however, necessarily lead to a loss of the organelle (31).…”

Section: Discussionmentioning

confidence: 99%

“…However, our proteomics dataset provided indirect clues that their function may be impacted. Isoprenoid synthesis is vital for T. gondii tachyzoites [33], and it has implication beyond the apicoplast, as prenylated proteins or isoprenoid precursors are involved in more general cellular processes including intracellular trafficking or mitochondrial respiration [83]. Isoprenoids are for instance important for synthesizing ubiquinone/coenzyme Q, and the single predicted mitochondrial candidate that was significantly less expressed upon TgNFS2 depletion is a putative UbiE/COQ5 methyltransferase, involved in synthesis of this co-factor [84].…”

Section: Discussionmentioning

confidence: 99%

See 1 more Smart Citation

Differential contribution of two organelles of endosymbiotic origin to iron-sulfur cluster synthesis and overall fitness in Toxoplasma

Pamukcu

Cerutti

Hem

et al. 2021

Preprint

View full text Add to dashboard Cite

Iron-sulfur (Fe-S) clusters are one of the most ancient and ubiquitous prosthetic groups, and they are required by a variety of proteins involved in important metabolic processes. Apicomplexan parasites have inherited different plastidic and mitochondrial Fe-S clusters biosynthesis pathways through endosymbiosis. We have investigated the relative contributions of these pathways to the fitness of Toxoplasma gondii, an apicomplexan parasite causing disease in humans, by generating specific mutants. Phenotypic analysis and quantitative proteomics allowed us to highlight striking differences in these mutants. Both Fe-S cluster synthesis pathways are necessary for optimal parasite growth in vitro, but their disruption leads to markedly different fates: impairment of the plastidic pathway leads to a loss of the organelle and to parasite death, while disruption of the mitochondrial pathway trigger differentiation into a stress resistance stage. This highlights that otherwise similar biochemical pathways hosted by different sub-cellular compartments can have very different contributions to the biology of the parasites, which is something to consider when exploring novel strategies for therapeutic intervention.

show abstract

Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Differential contribution of two organelles of endosymbiotic origin to iron-sulfur cluster synthesis and overall fitness in Toxoplasma

Pamukcu

Cerutti

Hem

et al. 2021

Preprint

View full text Add to dashboard Cite

show abstract

“…DC-9236 is showing higher elimination in the second life cycle. The types of compounds which are not effective at the first cell cycle, thus causing a delayed parasite death, are known to target apicoplast which is a vestigial chloroplast-like organelle (Kennedy et al, 2019b).…”

Section: Dc-9237 Is a Fast-acting Compoundmentioning

confidence: 99%

DeepMalaria: Artificial Intelligence Driven Discovery of Potent Antiplasmodials

et al. 2020

View full text Add to dashboard Cite

Antimalarial drugs are becoming less effective due to the emergence of drug resistance. Resistance has been reported for all available malaria drugs, including artemisinin, thus creating a perpetual need for alternative drug candidates. The traditional drug discovery approach of high throughput screening (HTS) of large compound libraries for identification of new drug leads is time-consuming and resource intensive. While virtual in silico screening is a solution to this problem, however, the generalization of the models is not ideal. Artificial intelligence (AI), utilizing either structure-based or ligand-based approaches, has demonstrated highly accurate performances in the field of chemical property prediction. Leveraging the existing data, AI would be a suitable alternative to blind-search HTS or fingerprint-based virtual screening. The AI model would learn patterns within the data and help to search for hit compounds efficiently. In this work, we introduce DeepMalaria, a deeplearning based process capable of predicting the anti-Plasmodium falciparum inhibitory properties of compounds using their SMILES. A graph-based model is trained on 13,446 publicly available antiplasmodial hit compounds from GlaxoSmithKline (GSK) dataset that are currently being used to find novel drug candidates for malaria. We validated this model by predicting hit compounds from a macrocyclic compound library and already approved drugs that are used for repurposing. We have chosen macrocyclic compounds as these ligandbinding structures are underexplored in malaria drug discovery. The in silico pipeline for this process also consists of additional validation of an in-house independent dataset consisting mostly of natural product compounds. Transfer learning from a large dataset was leveraged to improve the performance of the deep learning model. To validate the DeepMalaria generated hits, we used a commonly used SYBR Green I fluorescence assay based phenotypic screening. DeepMalaria was able to detect all the compounds with nanomolar activity and 87.5% of the compounds with greater than 50% inhibition. Further experiments to reveal the compounds' mechanism of action have shown that not only does one of the hit compounds, DC-9237, inhibits all asexual stages of Plasmodium falciparum, but is a fast-acting compound which makes it a strong candidate for further optimization.

show abstract

“…This organelle is characterized by four membranes and plays a key role in major metabolic pathways, such as generation of isoprenoid, fatty acids, and heme ( 13 ). The essentiality of the mitochondrion and apicoplast in apicomplexan parasites is demonstrated by the fact that these organelles are well-established drug targets ( 14 , 15 ). A recent subcellular atlas of the Toxoplasma proteome confirmed a significant overrepresentation of essential functions in these endosymbiotic organelles ( 16 , 17 ).…”

Section: Introductionmentioning

confidence: 99%

Organelle Dynamics in Apicomplexan Parasites

Verhoef

Meissner

Kooij

2021

mBio

View full text Add to dashboard Cite

Apicomplexan parasites, such as Toxoplasma gondii and Plasmodium falciparum , are the cause of many important human and veterinarian diseases. While T. gondii tachyzoites replicate through endodyogeny, during which two daughter cells are formed within the parental cell, P. falciparum replicates through schizogony, where up to 32 parasites are formed in a single infected red blood cell and even thousands of daughter cells during mosquito- or liver-stage development.

show abstract

Delayed Death by Plastid Inhibition in Apicomplexan Parasites

Cited by 41 publications

References 100 publications

Differential contribution of two organelles of endosymbiotic origin to iron-sulfur cluster synthesis and overall fitness in Toxoplasma

Differential contribution of two organelles of endosymbiotic origin to iron-sulfur cluster synthesis and overall fitness in Toxoplasma

DeepMalaria: Artificial Intelligence Driven Discovery of Potent Antiplasmodials

Organelle Dynamics in Apicomplexan Parasites

Contact Info

Product

Resources

About