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Master of antimalarial resistance

24.09.2004


A malaria parasite gene called pfcrt, already confirmed as the culprit behind resistance to the drug chloroquine in the malaria species Plasmodium falciparum, may be responsible for resistance to several other antimalarial drugs as well, a team of researchers reports in the 24 September issue of the journal Molecular Cell.



The discovery of pfcrt’s "central role" in malarial drug resistance could "help in the development of new therapeutic strategies that are effective against chloroquine-resistant parasites," said David Fidock of Albert Einstein College of Medicine, one of the lead authors of the paper.

Nearly three million people, mostly children, die from malaria each year. Chloroquine is one of the most affordable and widely used antimalarial drugs available, but chloroquine-resistant malaria has become an increasingly serious problem in the developing world, with death rates rising as a consequence.


The experiments conducted by Fidock and colleagues suggest that previously unknown mutations in the pfrct gene are associated with Plasmodium falciparum’s resistance to halofantrine and amantadine. The two drugs are used to treat mild to moderate cases of chloroquine-resistant malaria. Fidock said pfcrt’s role in halofantrine and amantadine resistance was "a big surprise actually, for both drugs. We thought initially that pfcrt was only critical for chloroquine."

The researchers uncovered the new pfcrt mutations after gradually creating strains of malaria resistant to halofantrine and amantadine treatment. As resistance to these two drugs increased, however, the parasites lost their resistance to chloroquine. This unusual pattern--gaining resistance to one drug while simultaneously losing resistance to another--may shed light on the exact role that pfcrt plays in resistance, according to Fidock and colleagues.

When a human is infected with malaria, the parasite lodges itself inside the red blood cells of its new host, drawing on the cells’ hemoglobin molecules for sustenance. As the parasite digests the hemoglobin inside a membrane pocket called the digestive vacuole, it creates a toxic byproduct called free heme. Normally, the parasite detoxifies the free heme by turning it into a product called hemozoin. As an antimalarial drug, chloroquine works by blocking this detoxification process.

The protein produced by the pfcrt gene is located in this digestive vacuole and may act as its gatekeeper. In chloroquine-resistant malaria, mutations in pfcrt may encourage chloroquine to "leak" out of the vacuole before it has a chance to stop the heme detoxification process. The pfcrt mutations seen in halofantrine and amantadine resistance seem to slow down this leak, restoring the parasite’s sensitivity to chloroquine therapy, the researchers suggest.

Fidock and colleagues note that one of the newly discovered pfcrt mutations can be found in a strain of malaria from Southeast Asia, suggesting their lab data have a parallel in the real world. The other members of the research team include Stephen Ward, Mathirut Mungthin and Patrick Bray of the Liverpool School of Tropical Medicine and Viswanathan Lakshmanan, David Johnson, and Amar Bir Singh Sidhu of Albert Einstein College of Medicine. The study was supported in part by the Wellcome Trust UK and BBSRC, the National Institutes of Health and the Ellison Medical Foundation.

David J. Johnson, David A. Fidock, Mathirut Mungthin, Viswanathan Lakshmanan, Amar Bir Singh Sidhu, Patrick G. Bray, and Stephen A. Ward: "Evidence for a Central Role for PfCRT in Conferring Plasmodium falciparum Resistance to Diverse Antimalarial Agents"

Heidi Hardman | EurekAlert!
Further information:
http://www.cell.com

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