How Parasite Genes Differ May Be Key to Chloroquine Resistance

May - June, 2008  |  Volume 7, Issue 3

A study led by a Fogarty grantee provides new insights into the evolutionary dynamics of malaria parasite genes, findings that could lead to more effective treatment.

a round map of the world with distribution of malaria depicted by blue areas across the southern half of the world. Photo credit: CDC

Chloroquine (CQ) is still the main drug used in malaria hotbeds of Asia and South America, even where the disease-carrying parasite Plasmodium falciparum has developed resistance. Because of resistance and the wide prevalence of malaria, CQ is being replaced in Africa by artemisinin combination therapy (ACT), though at a slow pace because of its expense.

The discovery, published in the June issue of Antimicrobial Agents and Chemotherapy, reports the genetic diversity patterns of two genes of P. falciparum (known as Pfcrt and Pfmdr1), which are thought to be susceptible to the drug.

"The main implication is: because chloroquine has been discontinued in Africa and replaced by other drugs, how is Pfmdr1 going to behave now at the genetic level?" said lead author Dr. Rajeev K. Mehlotra of the Center for Global Health and Diseases at the Case Western Reserve University School of Medicine.

"These results suggest that variation at Pfcrt and Pfmdr1 loci in both Asian and African parasite populations is generated and/or maintained via substantially different mechanisms. Since Pfmdr1 mutations may be associated with resistance to artemisinin combination therapies that are replacing CQ, particularly in Africa, it is important to determine if, and how, the genetic characteristics of this locus change over time," the authors concluded.

The study analyzed 460 blood samples from malaria patients from diverse regions of Asia and the South Pacific (Papua, New Guinea, Indonesia, Laos and India); Africa (Kenya, Uganda and Ghana) and South America (Brazil, Colombia and Guyana).

"This is a great example of molecular epidemiology helping to define the malaria parasite's resistance to drugs. We need to track resistance exceedingly carefully as ACTs are being introduced and other antimalarials phased out." said Dr. Joel G. Breman, a senior scientific advisor at Fogarty and guest editor of three supplements on the American Journal of Tropical Medicine and Hygiene on "The Intolerable Burden of Malaria."

Discordant Patterns of Genetic Variation at Two Chloroquine Resistance Loci in Worldwide Populations of the Malaria Parasite Plasmodium falciparum. Rajeev K. Mehlotra, Gabriel Mattera, Moses J. Bockarie, Jason D. Maguire, J. Kevin Baird, Yagya D. Sharma, Michael Alifrangis, Grant Dorsey, Philip J. Rosenthal, David J. Fryauff, James W. Kazura, Mark Stoneking, and Peter A. Zimmerman. Antimicrobial Agents and Chemotherapy, June 2008, p. 2212-2222, Vol. 52, No. 6.

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