Malaria’s Best Defense Is Also Its Achilles’ Heel

Mutations to a protein that enables the malaria parasite to evade several anti-malarial drugs can make it vulnerable to other drugs, a study has found.

AsianScientist (Jul. 26, 2016) – Researchers in Australia have found that one of the malaria parasite’s best weapons against drug treatments is also its Achilles’ heel.

Mutations to the Plasmodium falciparum chloroquine resistance transporter (PfCRT), a protein that enables the parasite to evade several anti-malarial drugs, can also make it vulnerable to other therapies such as the antimalarial quinine or the antiviral amantadine.

The findings, published in PLOS Pathogens, may help to prolong the use of several anti-malarial drugs in treating the mosquito-borne disease, which kills 600,000 people around the world each year.

According to lead researcher Dr. Rowena Martin at The Australian National University (ANU), the interactions of the modified protein with certain drugs were so intense that the protein was unable to effectively perform its normal role, which was essential to the parasite’s survival.

In their paper, the research team also describes two possible mechanisms for the observed drug hypersensitivity, from studying the protein in Xenopus frog oocytes and in its native environment within the parasite.

“We also found that the changes that allow the protein to move chloroquine away from its anti-malarial target simultaneously enable the protein to deliver other drugs to their anti-malarial targets,” she said.

“The other important phenomenon we found is when the protein adapts itself to fend off one of these drugs, it is no longer able to deal with chloroquine and hence the parasite is re-sensitized to chloroquine.”

Martin added that if chloroquine or a related drug is paired with a drug that is super active against the modified protein, no matter what the parasite tries to do, it is “checkmate” for malaria. This hypersensitivity phenomenon also occurs in other drug-resistant pathogens, such as bacteria, and in cancer cells.

PhD student Ms. Sashika Richards, who is the first author of the study, said prolonging the use of existing drugs was crucial, as it would give scientists time to find the next anti-malarial drug. The current frontline anti-malarial drug, artemisinin, is already failing in Asia, and no alternatives are currently available.

The article can be found at: Richards et al. (2016) Molecular Mechanisms for Drug Hypersensitivity Induced by the Malaria Parasite’s Chloroquine Resistance Transporter.


Source: Australian National University.
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