BioWorld International Correspondent

LONDON - A change in a single amino acid is all that lies between the malaria parasite's susceptibility to the antimalarial drugs called artemisinins and widespread resistance, researchers believe.

A new study into the mechanism of action of the artemisinins has uncovered an amino acid in a "gatekeeper position" on a key molecule of the parasite, which determines whether the artemisinins can knock out the protein target.

The work could allow scientists to monitor malarial infections in the field, to identify resistance to the artemisinins before it has a chance to take hold and spread geographically. It also might make it possible to design new drugs that aim specifically to counter resistance to artemisinins even before resistance occurs.

Sanjeev Krishna, professor of molecular parasitology and medicine at St. George's Hospital Medical School in London, told BioWorld International: "There is no evidence at the moment for resistance in malarial parasites to this class of antimalarial drugs. But we know this parasite has become resistant to every other type of antimalarial that has ever been used. It is now clear that there is a chance that the parasites could become resistant to the artemisinins, too."

An account of the study appeared in the June 5, 2005, issue of Nature Structural and Molecular Biology in a paper titled "A single amino acid residue can determine the sensitivity of SERCAs to artemisinins."

There are about 500 million cases of malaria each year, and the disease claims an estimated 1 million to 3 million lives annually, most of them children in sub-Saharan Africa. The most severe form of malaria is caused by the parasite Plasmodium falciparum; Plasmodium vivax also causes considerable morbidity.

The artemisinins are the most important class of antimalarial drugs. They were discovered by Chinese scientists in the 1970s and are derived from the plant known as sweet wormwood (Artemisia annua). They have been used against malaria without any reports of resistance for more than 10 years.

Exactly how the artemisinins work has not been easy to establish. They contain a highly reactive structure called an endoperoxide bridge, which, some researchers suggested, has an effect by reacting with parasite proteins.

Two years ago, though, Krishna and his group showed that the class of drugs acts by interfering with a calcium pump in the parasite. But it had no effect on similar pumps that are found in mammalian cells.

Since then, the team identified a similar compound, called thapsigargin, which inhibits the calcium pumps of both malarial parasites and mammalian cells. That allowed the scientists to identify a region of the malarial calcium pump that seems to determine susceptibility to the artemisinins.

Krishna said: "We have now shown that the reason why the artemisinins hit the malarial calcium pump but not ours depends on very subtle differences in the sequence between the two pumps. If you change the gatekeeper' amino acid, the pump becomes completely resistant to the drug."

The amino acid concerned, which is normally a leucine, lies at position number 263 in the calcium pump protein. Krishna and his colleagues mutated the protein so that a different amino acid appeared in that position. In the calcium pump of Plasmodium vivax, changing the amino acid increased sensitivity to the artemisinins by a factor of three, while in Plasmodium berghei (a form of malaria that infects rodents), it decreased sensitivity by a factor of three.

Krishna added: "We found that you could change the sensitivity or resistance of the pump to the drug, depending on which amino acid we replaced the leucine with at position 263 in the protein."

An important next step, he said, would be to find out if the changes in susceptibility that the team observed also can take place in the parasites themselves. The studies reported in Nature Structural and Molecular Biology were carried out in a model system of Xenopus eggs.

A final experiment involved testing a potent derivative of the artemisinins, called artemisone, which is under clinical development at the Hong Kong University of Science and Technology. The parasite calcium pumps that Krishna's team had made resistant to other artemisinins were, unfortunately, also resistant to artemisone.

Krishna concluded: "My guess is that it is only a matter of time before the malaria parasite develops resistance to the artemisinin class of drugs. But we have now got the means to design better drugs, and to develop diagnostic tests to identify resistant strains as they arise."