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A Key to Resistance?

How malaria parasites evade first-line drugs

Malaria parasites are rapidly developing resistance to front-line drugs such as piperaquine (PPQ), threatening to undo years of progress in reducing deaths from the disease. But new pictures captured with single-particle cryo-electron microscopy are giving researchers clues about how to combat that resistance.

PPQ has been used all over the world to treat people infected with the malaria parasite. In combination with artemisinin, PPQ has helped slash the number of malaria-related deaths from over 1 million in 2004 to an estimated 435,000 in 2017.

Researchers at Columbia University found that the source of PPQ resistance is a protein in the malaria parasite called PfCRT, the same protein that had mediated resistance to the former first-line drug, chloroquine (CQ).

CQ and PPQ work by entering the parasite's digestive vacuole and altering it so that the parasite poisons itself on its own toxic waste product, formed from digested hemoglobin. PfCRT is located in the vacuole's membrane, and the location of mutations—inside a central cavity of PfCRT—reaffirm the observation that resistant parasites use variant forms of this protein to expel the drug out of the vacuole.

"It looked like the protein spits the drug out of the parasite's stomach," says Filippo Mancia, PhD, one of the lead researchers, "keeping it away from its target."

By making other mutations in the protein and testing their drug binding and transport abilities, the researchers found that only mutations in the protein's central cavity give PfCRT the ability to expel the drug from the vacuole.

"Getting ahead of the 'drug resistance curve' by knowing where to look in the parasite's genome will be critical to identifying where resistance arises and having time to move to alternative treatment strategies," says David Fidock, PhD, co-leader of the investigation.

"We may be able to restore the efficacy of these drugs with an agent that entirely blocks the capacity of this protein to transport anything," says Fidock. "That would make PPQ and the earlier first-line drug chloroquine fully functional."

Source: ScienceDaily, November 27, 2019

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