To Curb Malaria Parasite, Scientists Look To Manipulate Reproductive System

Drexel University scientists recently reported on the mechanism of two small-molecule antimalarial drugs: they cause a sodium influx which triggers an increase of cholesterol in the parasite’s plasma membrane, causing it to be less flexible and unable to traverse through the narrow convolutions in the human bloodstream. The drugs also trigger a premature reproduction cycle in the parasite, rendering it inert.

 

 

There are several drugs being researched that interrupt the parasite’s reproduction cycle. In 2014, Akhil Vaidya, PhD, professor at Drexel University’s College of Medicine and director of the Center for Molecular Parasitology published a study describing pyrazoleamides, a class of drugs which disrupts parasitic intracellular sodium homeostasis, causing the cells to swell and erupt.  

The new 2016 study published in PLOS Pathogens shed light on the more complex cascade of events followed by the drug-induced sodium influx, leading to changes in the parasite’s plasma membrane, or outer skin, and triggering a premature life cycle. Vaidya told Drexel Now,  “Nobody suspected something like this to be the mode of action. The mechanism is a lot more complicated and interesting than we originally thought.”

In the 2016 study, researchers focused on two different small molecules, pyrazoleamide and spiroindolone- which is undergoing clinical trials to combat the Plasmodium falciparum (P. falciparum) parasites. According to the World Health Organization, “P. falciparum is the most deadly malaria parasite and the most prevalent in Africa, where malaria cases and deaths are heavily concentrated.” In 2015, there were over 214 million estimated cases worldwide, and it claimed over 400,000 lives, mainly African children.

Although the two classes of drugs contain different molecular structures, they both trigger an intracellular sodium influx within the parasite, which eventually kills the pathogen. Until today, scientists did not understand the complex series of molecular events that lead to the destruction of the parasite.

To shed light on this question, researchers studied the pre and post-antimalarial effects on the parasite’s’ plasma membrane. Unlike other plasma membranes, including human cells, the parasite’s plasma membrane contains a low level of cholesterol, which is a major component of most other membranes. Scientists hypothesized that one reason for the low cholesterol content in the parasitic plasma membrane is that it reduces rigidity which allows it more flexibility as it traverses through the host’s circulation system, and allows the parasite to manage stress as it passes through tight spaces in the blood vasculature. They propose that the sodium influx triggered by the antimalarial drugs cause an increased cholesterol uptake in the plasma membrane, subsequently the plasma membrane becomes more rigid, rendering the parasite vulnerable to removal and/or damage from the host’s circulatory system.

Researchers measured the presence of cholesterol in the parasite’s plasma membrane using a cholesterol-dependent detergent. They found that pyrazoleamide and spiroindolone appeared to increase the uptake of cholesterol in the parasite’s plasma membrane, which was reversible upon removal of the antimalarial drugs. “We believe that the cholesterol makes the parasite rigid, and then the parasite can no longer pass through very small spaces in the bloodstream,” Vaidya stated, adding that if the parasite cannot traverse through erythrocytes, it cannot continue through the reproductive cycle.

 

Within two hours of exposure to the drugs, scientists observed apparent nuclear division, marked by the appearance of organelles and inner membrane complexes. However, these morphological changes occurred without DNA synthesis, a necessary component of cell division and viability. Researchers hypothesized that the sodium influx is part of a normal signaling process during the reproductive cycle of malaria parasites. The sodium influx caused by the antimalarial drugs trigger the parasite’s premature division and death. “This whole cascade of events is triggered by these drug treatments. The parasite is not ready to divide yet, so it can not survive. It is like premature delivery of an infant,” Vaidya said.

 

One of the great challenges researchers are anticipating is the emergence of P. falciparum parasites resistant to currently effective therapies. To combat this, scientists must develop a robust pipeline for antimalarial drugs. Viday and his research team hope to identify new potential drug candidates by understanding the mechanisms by which these classes of drugs cause the demise of the malaria parasite. He noted that the most effective antimalarial defense will be a combination of therapies. “We want to find the best ways to keep new drugs effective as long as we can.”

 

 

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