Imaging study reveals how malaria parasites bypass antimalarial drugs

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Over the past decade, the use of artemisinin and piperaquine (PPQ) has significantly decreased the number of deaths from malaria. However, rapid dissemination of PPQ resistance throughout Southeast-Asia has threatened the effectiveness of this drug, which could be putting thousands of lives at risk.

Published in Nature, researchers from Colombia University Irving Medical Center (CUIMC; CO, USA), report that imaging studies have highlighted how protein mutations within the parasite result in efflux of these antimalarial drugs.

“Uncovering the molecular underpinnings of resistance is essential to prolonging the effectiveness of current drugs and developing new ones,” stated author David Fidock (CUIMC).

Elucidating antimalarial resistance

As PPQ enters the parasite digestive vacuole, it binds to an essential parasite protein responsible for heme detoxification during digestion. This results in the parasite ‘poisoning itself’ with the by-products of its metabolism.

Chloroquine resistance transporter (pfcrt) is a malarial protein situated in the digestive vacuole. Mutations previously been identified in pfcrt have been demonstrated to result in both chloroquine and PPQ efflux from the intracellular digestive vacuole membrane, inhibiting the drug’s mechanism of action.

In this study, the researchers tagged pfcrt with an antibody fragment and visualized the tagged protein using single-particle cryo-electron microscopy, which allowed the team to generate a 3D model. The team also created nano-sized lipid disks to stabilize the protein and ensure it was in its nearly natural state for observation.

The imaging suggested that mutations in the protein’s central cavity give pfcrt the ability to expel the PPQ from the vacuole. Biochemical testing of transport abilities with mutant versions of pfcrt further confirmed that only mutations within the central cavity resulted in the drug efflux from the vacuole.

“It looked like the protein spits the drug out of the parasite’s stomach,” commented author Filippo Mancia (CUIMC), “keeping it away from its target.”

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