Malaria drug resistance gene identified

A US research group headed by Tom Wellems of the US National Institute for Allergy and Infectious Diseases (NIAID) announced at the end of October that they had identified a gene which mutates to makes the most lethal of the malaria parasites, Plasmodium falciparum, resistant to chloroquine. The gene, dubbed pfcrt, is on chromosome 7, and codes for a protein on the surface of the parasite’s stomach. The NIAID group identified the pfcrt gene by crossing chloroquine-sensitive and chloroquine-resistant species of the parasite and by using molecular biology techniques to locate the gene.

Chloroquine is the cheapest of the malaria drugs, and together with DDT spraying to kill mosquitoes, was expected to help eradicate malaria in the 1950s to 1970s. But resistance to chloroquine developed in the mid-1950s in South-East Asia and in South America in 1959, reaching Africa in the 1970s and 1980s, and now extends over most of the tropical world. In Central America, North Africa and China P. falciparum is still sensitive to chloroquine.

David Warhurst, Professor of Protozoal Chemotherapy at the London School of Hygiene and Tropical Medicine, told the Bulletin: ‘‘It seems clear that this is a very important result. The level of resistance that the mutations [identified in pfcrt] create is low, but it may open the gate to higher resistance by additional mutations.’’

Exactly how the gene works and how the mutation creates chloroquine resistance is still a puzzle. A malaria parasite feeds on its host’s haemoglobin, producing the waste product hemin, which is toxic to the parasite. Normally the hemin is chemically changed into a form the parasite can eliminate. But chloroquine, as well as several other antimalarial drugs, including amodiaquine, quinine, mefloquine and halofantrine, combine with the hemin and interrupt the transformation process, leaving more toxic hemin that kills the parasite. The pfcrt gene seems to make a protein, PfCRT, which sits on the wall of the parasite’s stomach, or food vacuole, and affects the acidity of the stomach contents, which in turn may interfere with how chloroquine combines with hemin. Alternatively, the protein may affect how much chloroquine enters the parasite’s stomach.

‘‘Only further research will tell us exactly what pfcrt and its mutations do, but its discovery changes the foundations for thinking about the whole process of chloroquine resistance,’’ Dr Wellems told the Bulletin. ‘‘There have been dozens of different theories, but now we have a specific molecule, PfCRT, to focus on.’’

Three years ago, the NIAID group reported that another gene, called cg2, was linked to parasite resistance to chloroquine. ‘‘This gene, however, was not clearly associated with chloroquine resistance in South America, and has now been ruled out as the cause of chloroquine resistance,’’ Dr Wellems said. ‘‘There is far more evidence pointing to the pfcrt gene, which seems to be linked to chloroquine resistance in Africa, Asia and Latin America.’’

The discovery of pfcrt holds promise for new drugs, according to Dr Wellems. ‘‘If we can mimic the action of chloroquine with another drug that blocks the pfcrt resistance mechanisms, it should have a long life.’’

Dr Wellems’ team included David A. Fidock of the Albert Einstein College of Medicine, in New York, and Paul D. Roepe, of Georgetown University.

Robert Walgate, London

World Health Organization Genebra - Genebra - Switzerland
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