Combating Anti-Malarial Resistance: The Preclinical Way

In 2016, there were 216 million reported cases of malaria. It has been estimated that at least half a million people die globally from malaria every year, and two-thirds of these are children under the age of 5 years1.

mosquito spray

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Malaria is an infectious disease transmitted by the mosquito. The symptoms are similar to those of influenza and vary in severity. Symptoms generally arise 1-2 weeks after being bitten by a mosquito carrying the parasite, but in some cases it can take up to a year for symptoms to develop, providing great opportunity for the infection to be transmitted to other individuals.

More than half of malaria cases are caused by the Plasmodium falciparum protozoa, which gives rise to the most serious form of the disease. Without prompt treatment, this type of malaria can lead to the rapid development of severe and life-threatening complications, such as breathing problems and organ failure.

There is ongoing global collaboration to eliminate deaths from malaria by the provision of protective netting and mosquito repellents in high-risk areas. Anti-malarial treatments to inactivate the protozoa so it cannot infect others also play a very important role in the control of this disease.

Treatment, however, is being increasingly hampered by the development of drug resistance in the causal protozoa. There is consequently ongoing research to develop novel, more effective anti-malarial drugs.

Plasmodium falciparum

Plasmodium falciparum is a unicellular protozoan that invades red blood cells (RBCs) and causes the most dangerous type of malaria. On entering a RBC it undergoes a series of morphological changes as it progresses through its developmental cycle, which is completed in only 48 hours2.

As it matures, the parasite takes on different distinct forms, through ring, trophozoite and schizont stages, before forming daughter merozoites. The new parasites are released as the RBC lyses and are ready to infect more RBCs and start the cycle again. A subset of the blood-stage parasites turn into gametocytes, via a multi-step maturation process, which facilitates parasite transmission via the mosquito.

The rapid growth and proliferation of the protozoa during its developmental cycle uses significant carbon and energy resources. Levels of glucose metabolism are thus high. Assays of glycolysis rate have shown that the trophozoites are especially metabolically active as they prepare for cell division3. This makes them vulnerable to anti-malarial drugs. In contrast, ring-stage parasites are less metabolically active and can better withstand antimalarial compounds.

The Plasmodium developmental cycle can remain dormant in the ring stage for many days or even weeks. It appears that this temporary period of dormancy allows the malaria parasites to recover from exposure to lethal doses of artemisinin-based antimalarial drugs. In order to halt further development of such drug resistance, it is necessary to identify a compound that can rapidly kill and eliminate ring-stage parasites.

Identifying novel anti-malarial drugs

With the increasing prevalence of malaria that is resistant to frontline anti-malarial drugs, there is a need to discover novel antimalarial compounds that are effective throughout the parasite’s lifecycle. In particular, a drug that is effective against the ring-stage parasites is needed.

Identifying such a compound has proved challenging since the ring stage is reached within the first 15 hours after infection and most antimalarial screening methods are designed as endpoint assays, such as parasite death following exposure to the drug. As such, they do not allow monitoring of the transition from ring-stage parasites to trophozoites.

It has now been realized that since measuring the level glycolytic activity provides an indicator of metabolic rate, it also provides information regarding the viability of the parasite at each stage of its developmental cycle. Based on this knowledge, a 13C NMR spectroscopy methodology has been devised for tracking the stage-specific effect of various antimalarial compounds by quantifying parasite glycolytic activity in real-time 4.

The glycolytic activity of Plasmodium falciparum in live human red blood cells was monitored with 13C NMR spectroscopy using a Bruker Avance NMR spectrometer. The data obtained were used to produce a high-resolution metabolic profile for the entire 48-hour developmental cycle of Plasmodium falciparum. This showed that RBCs infected with Plasmodium falciparum consume around 20 times more glucose than ring-stage parasites.

The blood cells were then exposed to a selection of mechanistically-distinct anti-malarial compounds (chloroquine, atovaquone, Cladosporium, DDD107498 and artemisinin) and the effect on the level of glycolysis assessed.

In this way, it was possible to track at which stages of the developmental cycle a drug killed the Plasmodium parasites. Since the assay could be performed in a very short timescale, the drug effect on specific developmental stages of the parasite could be observed. The data confirmed that ring-stage parasites were better able to tolerate anti-malarial drugs than the trophozoites.

It is hoped that this NMR assay will facilitate the screening of potential anti-malarial compounds and enable the identification of novel drugs that are capable of rapidly killing ring-stage Plasmodium falciparum to give us the upper hand in the battle against malaria.

References

  1. WHO World Malaria Report 2017
  2. Miller LH, et al. Malaria biology and disease pathogenesis: insights for new treatments. Nat. Med. 2013;19:156–167.
  3. van Niekerk DD, et al. Targeting glycolysis in the malaria parasite Plasmodium falciparum. FEBS. J. 2016;283:634–646.
  4. Shivapurkar R, et al. Evaluating antimalarial efficacy by tracking glycolysis in Plasmodium falciparum using NMR spectroscopy. Scientific Reports 2018;8:Article number: 18076.

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Last updated: Sep 3, 2019 at 10:47 AM

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