Researchers at the Dartmouth Medical School, demonstrated how malaria parasites form mutations that make them stubbornly resistant to drug therapy.

Investigators developed disease models using yeast and successfully introduced five mutations that make malaria resistant to the anti-malarial drug, Atovaquone.

" This is the first quantitative explanation for malaria's drug resistance," said Bernard Trumpower, at Dartmouth Medical School and head of the study. " In addition to confirming the belief that the resistance was due to these mutations, we have created a practical research tool to design new, improved versions of the drug using these resistant strains."

Malaria, transmitted by Plasmodium falciparum, a parasite carried by mosquitoes, has developed resistance to almost every anti-malarial drug introduced in the past 30 years.
Although Atovaquone is one of the most recent drugs on the market, there is significant evidence that malaria parasites are quickly developing resistance to that drug as well.

According to WHO estimates, 40% of the world's population are currently at risk of the disease and approximately 2 million people, mostly children, are killed by malaria annually worldwide.

Investigating ways to counter the mutations and sustain the efficacy of anti-malarial drugs, Trumpower and his colleagues continued their work on previous studies using yeast enzymes to explore Atovaquone resistance.
It is not possible to grow enough malaria parasites to isolate and study the respiratory enzyme cytochrome bc1 complex, which the parasites need to live and multiply.
A protein subunit of the bc1 complex is where the malaria parasite mutates to counter anti-malarial drug therapies.
Yeast is an effective resource because it can be safely grown in large quantities and can be easily modified to take on the qualities of more dangerous pathogens, without risking human infection.

When the researchers genetically transferred mutations into the yeast surrogates, the yeast acquired resistance to Atovaquone just as the malaria parasites had done.
The team was then able to apply computerized modeling techniques to illustrate exactly how the drug interacted with the cytochrome bc1 complex on a molecular level.

With this new understanding of how the parasites were able to counter the effects of Atovaquone, researchers can now design new anti-malarial drugs with features making the appearance of resistance more unlikely.

The study has been published in Journal of Biological Chemistry.

Source: Dartmouth-Hitchcock Medical Center, 2005


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