Fosmidomycin

The high-tech drudge work of sequencing genes is starting to pay dividends. Using newly discovered genetic clues about a parasite that causes malaria, scientists in Germany have cured the disease in mice with two drugs previously used to combat bacterial infections in people. The finding suggests these drugs might successfully treat people who have malaria.

The most severe cases of the disease stem from Plasmodium falciparum, the single-cell parasite that has been on scientists' hit list since they first discovered malaria was carried by mosquitoes. For the past century, P. falciparum has withstood the best scientific weaponry, ranging from quinine to synthetic vaccines.

The new approach exploits a molecular chainreaction that ultimately produces isoprenoid compounds, which organisms need to survive. This construction process, or pathway, relies on specific enzymes that facilitate each step in the synthesis of isoprenoids.

Scientists have been looking for an isoprenoid pathway in malaria parasites. However, it has become clear in recent years that the pathway used by animals and plants is missing in P. falciparum. Some algae, bacteria, and plants, however, make isoprenoids by employing another set of enzymes.

The researchers in Germany sought such a pathway in P. falciparum by plowing through its genome. There, they found genes that encode two components in the isoprenoid pathway used by algae, bacteria, and plants, says study coauthor Jochen Wiesner, a physician and biologist at Justus Liebig University in Giessen, Germany. These enzymes are DOXP synthase and DOXP reductoisomerase.

Meanwhile, other research has shown that a little-known antibiotic destroys DOXP reductoisomerase. The drug, called fosmidomycin, was first synthesized by Fujisawa Pharmaceuticals of Japan. For Wiesner and his colleagues, the drug and its derivative, FR900098, became obvious candidates for weapons against the parasite's pathway.

Tests against P. falciparum in laboratory dishes showed that shutting down the pathway with the antibiotics kills the parasite, the researchers report in the Sept. 3 SCIENCE.

Because P. falciparum grows only in primates, the team infected several groups of mice with the parasite Plasmodium vinckei, which causes lethal malaria in mice. The mice were then given FR900098 or fosmidomycin. Moderate doses of either drug cured the mice outright in 8 days, whereas untreated mice died of malaria within that time.

Mice receiving the drugs orally needed greater doses to achieve the same effect that an injection provided. Nevertheless, "these were still safe amounts," Wiesner says.

Whether fosmidomycin or its derivative will kill P. falciparum in a person remains unproved. The researchers don't know if the parasite, once it has infected a red blood cell, relies exclusively on the DOXP pathway to manufacture isoprenoid compounds.

There's no evidence that the alternative pathway in animals and plants exists in P. falciparum, says study coauthor Hassan Jomaa, a physician at Justus Liebig University. "Whether these isoprenoids are synthesized de novo by the parasite or taken from the [host] medium is not yet definitively proven," Jomaa notes. "However, our data suggest that at least some essential isoprenoids are synthesized de novo."

"Sole dependence on the DOXP pathway would probably raise the value of this pathway's enzymes as drug targets," says Robert G. Ridley of the World Health Organization in Geneva, writing in the same issue of SCIENCE.

This mouse study "shows that the malaria genome project is bearing fruit," says Stephen L. Hoffman of the Naval Medical Research Center in Bethesda, Md. He is a participant in the international consortium that has been sequencing the P. falciparum genome and posting completed portions on the Internet for researchers, such as the German team, to use.

"We hoped to promote this exact type of finding," Hoffman says.

Wiesner says that the scientists are prepared to test the drugs on malaria patients because the toxicological data on fosmidomycin already indicate that it's safe to use. In fact, the data suggest that effective doses would be less than the amounts that physicians would prescribe to fight bacterial infections.

COPYRIGHT 1999 Science Service, Inc.
COPYRIGHT 2000 Gale Group