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How Do Anti-Malarial Drugs Really Work? NMR Sheds Light on this Critical Issue

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Malaria is one of the most severe public health problems worldwide, being responsible for around 500,000 deaths every year1. It is a leading cause of death and disease in many developing countries, where young children and pregnant women are the groups most affected. Malaria imposes significant social and economic costs to individuals and governments, and the direct costs (for example, illness, treatment, premature death) have been estimated to amount to at least US$ 12 billion per year2.

One of the United Nations' 17 Sustainable Development Goals is to end epidemics such as malaria by 2030, but a key challenge facing this goal is the increasing prevalence of malaria that is resistant to frontline antimalarial drugs. So, there is a need to discover novel antimalarial compounds to help fight this disease on a global scale.. Nuclear magnetic resonance (NMR) is helping scientists unlock this discovery.

The parasite causing more than half of all cases of malaria in humans is the unicellular protozoan Plasmodium falciparum. Most parasites, including P. falciparum, have complex life cycles that involve development through a series of distinct forms. Once it invades a red blood cell (RBC), it undergoes a 48 hour developmental cycle, which ultimately results in the breakdown of the RBC to release new parasites that can invade another RBC straight away.

This development process requires significant energy resources and is therefore associated with high glucose metabolism, making metabolic activity a good indicator of parasite viability. More metabolically active stages of the life cycle are more vulnerable to antimalarial drugs, whereas less metabolically active stages are better able to withstand them. Understanding the effect of antimalarial interventions on the different distinct stages of the parasite's life cycle is therefore critical to developing effective treatments.

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It has been shown previously that the glycolytic activity of live RBCs infected with P. falciparum can be monitored in real time using NMR spectroscopy. Researchers have now used this technique to investigate the effects of antimalarial compounds on the distinct stages of the malaria parasite inside RBCs3. NMR spectra showed that RBCs infected with P. falciparum consume around 20 times more glucose than dormant stage parasites. The effects of various antimalarial drugs with different modes of action, including chloroquine, atovaquone, cladosporin, DDD107498 and artemisinin, on the levels of glycolysis were then investigated.

The research found that dormant stage parasites were more tolerant to antimalarials than more metabolically active stages of the parasite life cycle - and it is this dormancy that could give rise to drug-resistant malaria. New fast-acting antimalarial compounds that are active against less metabolically active parasites are therefore a research priority.

Our NMR assay used in this study is a powerful tool in the ongoing global battle against malaria, helping the UN achieve its 2030 goals. The ADVANCE NMR spectrometer facilitates screening to identify potential new drug candidates that reduce the viability of more drug-resistant parasites to, ultimately, stop the disease taking hold.

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References

 1. WHO World Malaria Report, http://www.who.int/malaria/publications/world-malaria-report-2017/en/ (2017).

2. Centers for Disease Control and Prevention (CDC) https://www.cdc.gov/malaria/malaria_worldwide/impact.html.

3. Shivapurkar R, et al. Evaluating antimalarial efficacy by tracking glycolysis in Plasmodium falciparum using NMR spectroscopy. Scientific Reports, 2018;8: Article number: 18076. https://www.nature.com/articles/s41598-018-36197-3#Sec8