Ring-stage growth arrest: Metabolic basis of artemisinin tolerance in Plasmodium falciparum

iScience, 2023 · DOI: https://doi.org/10.1016/j.isci.2022.105725 · Published: January 20, 2023

Simple Explanation

Malaria parasites are becoming resistant to artemisinin, a key drug. This study found that resistant parasites slow their growth in the early ring stage. The researchers created artemisinin-resistant parasites and studied their metabolism. They discovered changes in energy production and amino acid usage. By manipulating these metabolic pathways, the researchers could alter the parasites' resistance to artemisinin, suggesting new drug targets.

Study Duration

Not specified

Participants

Not specified

Evidence Level

Not specified

Key Findings

1
PfKelch13 mutant parasite lines exhibit reduced susceptibility to DHA and prolonged ring stage.
2
Metabolomics screening points to altered energy metabolism with metabolic plasticity in artemisinin-resistant parasites.
3
Altering metabolic flow or chemical inhibition confirms the metabolomics screening results, influencing DHA susceptibility.

Research Summary

This study investigates the metabolic mechanisms underlying artemisinin resistance (ART-R) in Plasmodium falciparum, focusing on the role of PfKelch13 mutations and ring-stage growth arrest. The research identifies significant alterations in the tricarboxylic acid (TCA) cycle, glycolysis, and amino acid metabolism in ART-R parasites, indicating adaptive metabolic plasticity. The findings suggest that growth arrestment associated with ART-R is attributed to metabolic remodeling, potentially triggering ART-R, and can be influenced by altering metabolic flow or chemical inhibition.

Practical Implications

Drug Target Identification

Identifies metabolic pathways as potential targets for novel antimalarial drugs.

Resistance Understanding

Provides insights into the metabolic adaptations that contribute to artemisinin resistance in malaria parasites.

Treatment Strategies

Suggests that targeting metabolic plasticity could be a strategy to overcome artemisinin resistance.

Study Limitations

1
The study used a mix of growth-arrested and dead parasites for metabolomics analysis.
2
Detailed targeted profiling aimed at quantitatively investigating the alterations for metabolites involved in related pathways had not been performed.
3
A brief validation for results obtained from this study should be considered in more filed isolates which were unavailable due to global COVID-19 situation.

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