Drexel University scientists have discovered an unusual mechanism for how two new antimalarial drugs operate: They give the parasite's skin a boost in cholesterol, making it unable to traverse the narrow labyrinths of the human bloodstream. The drugs also seem to trick the parasite into reproducing prematurely.

 

Malaria is a mosquito-borne disease caused by Plasmodium parasites. After a person is bitten, the parasite invades the victim's red blood cells. There, it eventually divides into daughter parasites, which continue to destroy each red blood cell they infect.

 

There are several drugs under development that interrupt this life cycle, including a class of compounds discovered in 2014 by Akhil Vaidya, PhD, a professor at Drexel University College of Medicine.

 

In their 2014 study, Vaidya and his research team found that these drugs increase levels of sodium within the parasites' cells, causing them to swell and erupt.

 

o explore this question, the researchers first tested the properties of the Plasmodium plasma membrane -- or the parasite's outer skin -- before and after exposure to antimalarial drugs. The Plasmodium membrane is unusual, because it contains very low levels of cholesterol, a major lipid component of most other membranes, including those of human red blood cells.

 

The researchers used a cholesterol-dependent detergent to detect the presence of lipids in the parasite membrane. They found that indeed both drug treatments appeared to add a significant amount of cholesterol to the Plasmodium plasma membrane.

 

Just two hours after treatment, the scientists also saw that many of the parasites showed fragmented nuclei and interior membranes, which are the precursors to cell division. But these changes happened without any sign that the parasite's genome had multiplied -- a step that is necessary for a cell to divide and survive.

 

The researchers hypothesize that sodium influx is a normal step during the malaria parasite's division. The antimalarial drugs prematurely induce this signaling event, and the parasite begins dividing before it should.

 

"The parasite is not ready to divide yet, so it can not survive. It is like premature delivery of an infant," Vaidya said. "This whole cascade of events is triggered by these drug treatments."

 

Malaria is the world's deadliest parasitic disease. It kills more than 300,000 people per year, according to the World Health Organization, and affects up to 300 million.