Malaria drug resistance



The principal malaria parasite, Plasmodium falciparum, develops resistance to three firstline antimalarial drugs when mutations occur in just one gene, say researchers in Australia. Moreover, resistance to a fourth andrelatively new antimalarial agent, artemisinin, can be influenced by mutations in the same gene, despite artemisinin being structurally different from the other three drugs.1

Alan Cowman at the Walter and Eliza Hall Institute of Medical Research in Melbourne and colleagues end a ten-year controversy that has included “fierce debate” with the publication of their findings. The team first isolated the P. falciparum pfmdr1 gene more than a decade ago and suggested it was involved in resistance. “This manuscript proves the role of the mutations in the pfmdr1 gene,” says Cowman.2 Mutations that affect the protein encoded by the gene, known as P-glycoprotein homologue 1 (Pgh1), prevent the drugs mefloquine, halofantrine and quinine from being concentrated in the parasite, allowing the parasite to grow even in their presence. The researchers also show that the same mutations influence the resistance of the parasite towards chloroquine in some strains and that they affect the sensitivity of the parasite to artemisinin. “This has important implications for the development of resistance to this new antimalarial agent,” says Cowman. Many researchers and physicians had pinned their hopes on artemisinin as an effective alternative to drugs which had met increasingly rapid parasite resistance. But the discovery that malaria-endemic areas now have populations of parasites with decreased sensitivity to artemisinin will reduce those hopes.

The mutations responsible for increased resistance in the pfmdr1 gene are found among parasite populations in Africa, South America and Asia which suggests that “there is selective pressure for their maintenance and spread”, say the researchers.



1Reed MB et al. Pgh1 modulates sensitivity and resistance to multiple antimalarials in Plasmodium falciparum. Nature, 2000, 403: 906–909.
2 Cowman A, personal communication.

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