An international research team led by Akhil B. Vaidya, PhD, professor in the Department of Microbiology & Immunology and director of the Center for Molecular Parasitology at Drexel University College of Medicine, has discovered a new class of drug compounds that could lead to potent new treatments in the battle against malaria. The results from preclinical studies are set for online publication in the November 25 edition of Nature Communications. The compounds affect the malaria parasites' ability to maintain adequate levels of sodium within their cells, leading to excessive water intake, which causes the parasites to burst.
Malaria is the world's deadliest parasitic disease. It is estimated to kill 600,000 people every year. Most of the deaths occur in children and pregnant women. Malaria's growing resistance to known drugs makes it all the more important to find new pathways to combat this disease, especially in developing countries.
Malaria-causing Plasmodium parasites grow within human red blood cells and are transmitted from person to person by mosquitoes. On infection, the parasite induces changes in the host cell membrane so that more nutrients are taken in, which triggers an increase in sodium concentration within red blood cells. However, the parasite keeps its own sodium levels low with the help of a protein (PfATP4), which pumps sodium out of the parasite. A class of antimalarial compounds known as spiroindolones affect this process and are currently being tested in clinical trials. However, the search for new classes is essential in the face of emerging drug resistance.
Vaidya and colleagues report that another class of compounds, called pyrazoleamides, disrupt sodium pumping and increase sodium levels in Plasmodium. This results in cell swelling and eventually, bursting. The compounds are potent inhibitors of Plasmodium growth in mice that have been engrafted with human red blood cells, leading to rapid parasite clearance when administered as a once-daily oral dose. After sustained pyrazoleamide exposure to induce resistance, fully resistant parasites appear at a very low frequency.
"The results of the study confirm that targeting sodium balance in Plasmodium is a promising approach for developing new antimalarial drugs," said Vaidya, the study's principal investigator. "Further research is needed to precisely identify the molecular target of the compounds and to determine whether these can be developed into other effective antimalarial drugs." The research from this global team was supported by Medicines for Malaria Venture, an international non-profit foundation, and the U.S. National Institutes of Health.
Drexel University College of Medicine's Center for Molecular Parasitology was formed in 2001 and has since become one of the largest academic groups in the country dedicated to researching, treating and preventing the spread of malaria.