Decoding anti-malarial drug resistance

The National Institute of Allergy and Infectious Diseases, part of the National Institutes of Health, has awarded a team of scientists led by GUMC $2,100,000 over five years to study mutations in two genes within the mosquito-borne protozoans that allow the parasites to rapidly overcome commonly used anti-malarial drugs.

"Drug resistant malaria kills about one million people a year. We must get a handle on this death toll by defining molecular mechanisms responsible for this increasing resistance," says the study's principal investigator, Paul D. Roepe, PhD, co-director of the Georgetown Center for Infectious Disease. He is professor in the departments of chemistry, and biochemistry and cellular & molecular biology.

The project, led by Roepe, includes co-investigators at Columbia University and the University of California, San Diego.

The Georgetown center is known for its leading work in malarial drug resistance and drug discovery. It was the first to purify proteins encoded by the genes (PfCRT and PfMDR1) that can mutate and make chloroquine and other drugs ineffective; and to describe how PfCRT works. In another project, investigators led by Roepe have performed large-scale screening to find effective ant-malarial drug combinations. A $4.8 million NIH grant in 2014 to Roepe and his colleagues is designed to find the fastest ways to identify highly potent and synergistic drug combinations for both treatment and prevention.

Roepe and his colleagues study Plasmodium falciparum (P. falciparum), the most lethal malarial parasite, responsible for 80-90 percent of malarial deaths. "There are now hundreds, if not thousands, of different strains of the parasite, due to use of different drugs around the world," he says. "What is used in East Africa may be different from that used in West Africa, or in Southeast Asia and South America. Resistant strains arise in each region based on the specific treatments used."

The two genes he studies -- PfCRT and PfMDR1 -- are the best understood markers for drug resistant malaria. Understanding more about them may lead to new therapies or to lethal combinations of existing therapies, Roepe says. "We cannot use a single drug anymore to treat malaria, we must use combinations. In the drug screening work, we have posted dozens drug combinations that are effective against drug resistant P. falciparum on the web so that researchers can study them further.

"We hope this new study will provide additional critical information for rapidly identifying the best new therapies," he says.