Two more articles on artemisinin resistance. The 'spread to Africa' theory is under grave threat.
Jamie
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Drug-resistant malaria on the rise, experts say
John Hopton for redOrbit.com – @Johnfinitum
April 19, 2015
Researchers have confirmed early signs of malaria parasites in Africa becoming more resistant to drugs, leading one person working on the study to fear a grave situation in future.
The traditional anti-malarial drug quinine has already been sidelined as the parasites carried by certain mosquitos became resistant to it over time. Now, other drugs commonly in use have been shown to be less effective than they once were.
Researchers at the London School of Hygiene & Tropical Medicine found that the most deadly form of the malaria parasite, Plasmodium falciparum, with a mutation to the gene ap2mu, was less sensitive to the antimalarial drug artemisinin.
A study in 2013, also led by the School, suggested an initial link between a mutation in the ap2mu gene and low levels of malaria parasites remaining in the blood of Kenyan children after they had been treated.
In the new study, published in Antimicrobial Agents and Chemotherapy, researchers genetically altered the malaria parasite in the laboratory to mutate the gene in the same way that had been observed in Kenya. They found the altered parasite was significantly less susceptible, needing a 32 percent higher artemisinin dose to be killed. The genetically altered parasite was also 42.4 percent less susceptible to quinine.
Much worse to come?
Earlier this year, a different research group discovered mutations in the gene kelch13. These were linked to reduced effectiveness of artemisinin treatment in South East Asia, where resistance usually begins, before spreading to Africa. However, there are now signs that a different route to drug resistance may be developing independently in Africa.
Lead researcher Dr. Colin Sutherland, Reader in Parasitology at the London School of Hygiene & Tropical Medicine, said: “Our findings could be a sign of much worse things to come for malaria in Africa. The malaria parasite is constantly evolving to evade our control efforts. We’ve already moved away from using quinine to treat cases as the malaria parasite has become more resistant to it, but if further drug resistance were to develop against our most valuable malaria drug, artemisinin, we would be facing a grave situation.”
Reason for optimism
However, there is optimism that the work will lead to greater understanding of how resistance occurs.
“We now know that the gene ap2mu is an important factor in determining how well our drugs kill malaria parasites,” Dr. Sutherland said. “We will be conducting laboratory and field studies to more accurately measure the impact of mutations in the ap2mu gene. We hope our findings will help understand resistance of malaria to drugs, and potentially be an important tool for monitoring malaria treatment in the future.”
Meanwhile, the International Business Times recently reported that a fast-working, single dose malaria drug developed in India was proven to be safe and effective in a series of tests on animals. The drug, triaminopyrimidine, is said to work against drug resistant strains of the malaria pathogen and has no known side-effects. After a few more lab tests, it will go for clinical trials in humans.
The World Health Organization estimates more than half a million people die from malaria every year, mostly children under five.
Read more at http://www.redorbit.com/news/health/1113373907/drug-resistant-malaria-on-the-increase-experts-say-041915/#sH1DjWjoLJeEU2FL.99
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Stressed to Death: Overcoming Drug-Resistance in Malaria Parasites
By Lauren Richardson
Posted: April 23, 2015
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.
http://blogs.plos.org/biologue/2015/04/23/stressed-to-death/
