Critical insight for new malaria treatment

Posted on September 5, 2011

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Parasite slows its growth to avoid toxic effects of anti-malaria drug:

La Trobe University research has revealed for the first time the mechanism by which the major anti-malarial drug now in use kills the malaria parasite.

It also helps us understand how a worrying resistance is being developed to these drugs by a pathogen that kills nearly 800,000 children each year.

The work was published recently in one of the world’s leading scientific journals, Proceedings of the National Academy of Science (PNAS), in the US.

Research team leader, biochemist Professor Leann Tilley, says the research points to new ways of boosting the action of antimalarial drugs to overcome this drug resistance problem.

Plasmodium falciparum is the most pathogenic human malaria parasite. It afflicts more than 200 million people world-wide.  Treatment relies heavily on combination therapies that include a drug called artemisinin, extracted from the wormwood herb.

‘Recent reports of decreased clinical effectiveness of artemisinin-based drugs are extremely concerning,’ she says. ‘It is therefore critical to understand the way artemisinin works so that we can overcome the pathogen’s resistance to this drug.’

Point of vulnerability

The new work by Professor Tilley, right,  and her team shows that artemisinin targets a point of critical vulnerability in the malaria parasite. ‘The parasite invades and grows within the red blood cells of its human victims,’ she says. ‘As it grows it consumes the haemoglobin of the red blood cell and releases an iron-containing pigment, called “haem”.’

Research from her laboratory demonstrates that supplies of this haemoglobin-derived iron are essential if artemisinin is to destroy the parasite. ‘Decreasing the production of this iron renders the parasites resistant to artemisinin,’ Professor Tilley says.  

 ‘We have also shown that the parasite can slow its growth and reduce its haemoglobin uptake rate in response to artemisinin treatment. This helps it avoid the toxic effects of artemisinin. Our work suggests that suspending haemoglobin digestion even for a short period will make parasites resistant to artemisinin. This is because artemisinin and its derivatives have very short half-lives.

Thus the La Trobe study not only gives an important insight into the nature of artemisinin action and resistance, but also suggests that new, longer-lived antimalarials will thwart this resistance mechanism.
Invades red blood cells

How is haemoglobin digestion important in the malaria parasite life cycle?

The malaria parasite, says Professor Tilley, invades and grows within the red blood cells of its human victims. ‘As it develops it needs space to grow and a source of amino acids that it can use as building blocks for proteins.

 ‘To satisfy these needs it consumes the haemoglobin of the red blood cell by continually taking up small packets of host cell cytoplasm and breaking down the haemoglobin, a process which releases the iron-containing pigment, haeme.

A number of antimalarial drugs target this point of critical vulnerability in the malaria parasite. Quinoline antimalarials interfere with the crystallization process leading to a build-up of toxic haeme.

She anticipates that use of endoperoxide antimalarial drugs with longer exposure in the bloodstream will prevent parasite escaping the drug’s effects via short-term growth arrest.

‘In this regard new synthetic endoperoxides with improved in vivo half-lives now under development hold great promise. Hence this work is critical for the design of better endoperoxide antimalarials,’ she says.
Almost all antimalarial drugs undergoing Phase II drug trials or beyond currently in the development pipeline include an endoperoxide component.

‘If we lose endoperoxide antimalarials to the scourge of drug resistance there is very little in the pipeline to replace this drug class,’ says Professor Tilley, who has now moved to the University of Melbourne where she continues her malaria research after having spent the last 22 years at La Trobe.