When battling any kind of resistance—even drug resistance—it pays to know thy enemy. In the case of the antimalaria drug atovaquone, DMS researchers recently confirmed the identity of "the enemy"—five specific mutations in an enzyme of the parasite that causes malaria. With this new understanding, the team hopes "to develop a drug that malaria cannot become resistant to," says biochemist Bernard Trumpower, Ph.D. "Malaria has become resistant to every drug that has been targeted to it."
Complex: Trumpower, who heads the lab that made the discovery, has spent years studying the cytochrome bc1 complex—the enzyme on which atovaquone acts—but only lately has he looked at its tie to malaria. About five years ago, a University of Michigan researcher phoned Trumpower to ask for his help studying atovaquone resistance in Pneumocystis pneumonia, once a major cause of death in AIDS patients. Soon Trumpower and his team learned that similar problems of resistance plagued the drug's effectiveness against malaria, too.
"In the case of Pneumocystis and malaria, there was evidence indicating that the resistance was due to mutations in the gene which codes for one of the proteins in this enzyme," Trumpower says. "That evidence was genetic coincidence." In other words, they'd found particular mutations in resistant
This graphic shows a mosquito, the vector for malaria, surrounded by molecular
models of the antimalarial atovaquone as it loses potency against resistant strains.
Pneumocystis and in resistant malaria parasites. Trumpower's lab modeled each of these mutations in yeast and then tested their resistance. The enzyme without the mutations was sensitive to the drug, while the enzyme with the mutations was resistant. "So we biochemically confirmed, or proved, what was suspected from genetic, coincidental, guilt by association," he says.
Atovaquone is a "relatively difficult compound to chemically synthesize,"
notes Trumpower. As a result, the drug (which goes by the brand name Malarone) is expensive and thus is taken mostly by Westerners who travel to regions where malaria is prevalent. Trumpower, however, believes a drug his team is developing, with the help of Dartmouth chemistry professor Gordon Gribble, Ph.D., will be easier to synthesize, cheaper, and better. "If we are going to succeed, we will know in a three- to five-year period," he adds.
Jennifer Durgin