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Stressed to Death: Overcoming Drug Resistance in Malaria Parasites

Artemisinin (public domain, via Wikimedia Commons)
Artemisinin (public domain, via Wikimedia Commons)

In recent decades the burden of malaria has greatly decreased. This is the result of both successful public health initiatives and widespread use of antimalarial therapeutics. Artemisinins are a family of drugs that have been incredibly effective against Plasmodium falciparum – the parasite that causes most cases of malaria – and are the foundation of antimalarial treatment worldwide. Unfortunately, strains of P. falciparum that are resistant to artemisinins have emerged and are spreading in South East Asia.


Containing and eliminating resistant parasites before they spread is critically important, and in a new research article published in PLOS Biology by Con Dogovski, Stanley C. Xie, Nectarios Klonis, and Leann Tilley at the University of Melbourne, working with colleagues from Thailand, Singapore and the USA, have identified two ways to overcome artemisinin resistance. They also develop a model, which can be used in clinical settings to predict whether a parasite has become resistant to artemisinins, providing a powerful tool to improve detection and treatment of malaria.


Plasmodium falciparum gametocyte among human blood cells
Plasmodium falciparum gametocyte surrounded by human blood cells (image credit: CDC).

Their research begins with determining how artemisinins kill P. falciparum. They found that normal parasites, when treated with artemisinins, exhibit the signs of cellular stress. When cells are stressed (and these can be any type of cell, from single-celled yeast, to parasites, to the cells that comprise your body), their proteins are often damaged. Stressed cells halt the production of new proteins and break down the damaged proteins, in a process known as the stress response. In the presence of a little stress, the stress response is able to prevent the cell from being inundated with damaged proteins, but in the face of a lot of stress, the stress response will be overwhelmed and the cells will die. What Dogovski, Xie, and colleagues found was that drug-resistant parasites resistant had a better stress response than sensitive parasites, which allowed them to tolerate and survive the stress-inducing artemisinin treatment.


The researchers identified two means to overcome the drug-resistant parasites’ increased stress tolerance. First, they blocked the way that cells degrade damaged proteins. Damaged proteins are broken down by a complex known as the proteasome. By treating drug-resistant parasites with artemisinins and a proteasome inhibitor they were able to stress the parasite and prevent its ability to protect itself from damaged proteins. Artemisinins and proteasome inhibitors, which are used in some cancer therapies, acted synergistically to kill the resistant parasites.


The second way they found to defeat drug resistance was to simply extend artemisinin treatment. Artemisinin treatment is usually only three days long, but the work presented in this article suggests that extending the treatment to 4 days, or splitting the doses, is effective at overcoming resistance. This concurs with research that recently found in an area with prevalent artemisinin-resistance that extending treatment to 6 days from 3 days was 97.7% effective at treating infections.


The WHO, in their Global Plan for Artemisinin Resistance Containment, states that “There is a finite window of opportunity to contain artemisinin resistance. If the current foci of artemisinin-resistant parasites are not contained or eliminated, the costs, both human and financial, could be great”. The research of Professor Tilley and colleagues makes an important step towards preventing the spread of drug resistance by identifying treatments that can kill resistant parasites.

Dogovski, C., Xie, S., Burgio, G., Bridgford, J., Mok, S., McCaw, J., Chotivanich, K., Kenny, S., Gnädig, N., Straimer, J., Bozdech, Z., Fidock, D., Simpson, J., Dondorp, A., Foote, S., Klonis, N., & Tilley, L. (2015). Targeting the Cell Stress Response of Plasmodium falciparum to Overcome Artemisinin Resistance PLOS Biology, 13 (4) DOI: 10.1371/journal.pbio.1002132

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