David Fidock, Ph.D.
Each year in Africa, malaria strikes some 350 million people, and more than a million people die. Most of those affected are young children. In the past few decades, drug-resistant malaria—especially forms of the disease that are resistant to chloroquine, the primary treatment for malaria since the late 1940s—has increasingly spread across several continents. Chloroquine is known for its safety, rapid efficacy and affordability, but the rise in the number of deaths and severe disease resulting from chloroquine resistant malarial infection, and the rapid spread of resistance to the affordable replacement drug pyrimethamine-sulfadoxine, leaves doctors little choice but to prescribe other more toxic and/or expensive drugs.
Clinical manifestations of this disease begin when the malaria parasite invades the red blood cells of the host and begins feasting on the cells’ hemoglobin molecules that are imported into the intracellular parasite’s digestive vacuole. As a result, free heme is created—a toxic byproduct that the parasite has to detoxify. This is achieved by converting heme into a crystalline product called hemozoin. As an antimalarial drug, chloroquine works by blocking this detoxification process.
Malaria’s renewed and devastating effect on global health has researchers racing to understand more about this disease. Dr. David Fidock, an associate professor of microbiology and immunology at the Albert Einstein College of Medicine of Yeshiva University and a 2003 recipient of a Burroughs Wellcome Fund Investigator in Pathogenesis of Infectious Disease Award, studies the genetic and molecular basis of malaria parasite resistance to drugs. He received his Ph.D. in microbiology from the Pasteur Institute.
In 2002, Dr. Fidock led an effort that conclusively demonstrated that chloroquine resistance (CQR) was attributed to a single parasite gene, called pfcrt. The idea that one gene rather than multiple genes could determine CQR represented a dramatic change in dogma. Researchers had earlier believed that CQR must involve multiple genes because it arose independently in the Old and New Worlds and was an exceedingly rare event: the first cases of chloroquine resistant malaria were detected in Asia and South America 12 years after the drug was introduced in the 1940s. It took another two decades for CQR to first appear in East Africa.
To modify the pfcrt DNA sequence in Plasmodium falciparum, which is the deadliest form of the malaria parasite, Dr. Fidock developed and applied precise molecular genetic approaches. This showed that as little as one amino acid change in the pfcrt gene’s protein could suffice to alter the drug response from chloroquine resistant to sensitive. Becoming chloroquine resistant however, required multiple mutations to occur in pfcrt.
The pfcrt gene’s protein in the digestive vacuole is thought to help regulate the physiological functions of the digestive vacuole inside which chloroquine becomes concentrated and binds to heme. However, in chloroquine resistant malaria, mutations in this gene may export chloroquine out of the vacuole before it has the opportunity to stop heme detoxification. Recently, Dr. Fidock found that pfcrt can also mutate to produce resistance to other antimalarials agents including halofantrine and, surprisingly, the anti-influenzal drug amantadine.
Dr. Fidock’s work further identified a number of other antimalarial drugs that became even more potent against parasites that had become chloroquine resistant. This unusual pattern—gaining resistance to one drug while simultaneously losing resistance to another—may shed light on the exact role that pfcrt plays in resistance, according to Dr. Fidock and colleagues. “Understanding the genetic basis of CQR and its effect on other antimalarial drugs has been pivotal in showing just how widespread CQR had become and has illustrated the urgency of implementing alternative antimalarials” Dr. Fidock said. He hopes that his research will stimulate further studies into other drugs as a means of controlling chloroquine resistant malaria.
From very early on in his research career, Dr. Fidock knew he wanted to apply science to address issues—such as improved protein yield in crops, or effective treatment of drug resistant infections—that would improve the well being of people living in poorer countries. “I saw how disproportionately little research was being done to address issues that directly affected impoverished regions of the world. Malaria in particular, and infectious disease in general, was a very attractive discipline for me because of its enormous impact on human health, especially in tropical regions” he said. “Malaria really suppresses Africa and keeps the continent very much at a subsistent level, where most people are struggling just to meet daily needs.”
By Russ Campbell, BWF communications officer