The evolution of chloroquine

The anti-malarial drug chloroquine lost its status as the leading treatment against malaria because of resistance developing in the mosquito-bourne parasite that causes this deadly disease. Now, new research indicates a different way of administering the drug could revive its use as an accessible antimalarial treatment and preventative.

Malaria claims the lives of more than half a million people each year around the world.

Malaria treatment was revolutionised in the 1930s with the discovery of  chloroquine. After about 10 years of use, mutations within Plasmodium falciparum, the parasite that causes malaria, developed and conferred resistance to the drug. Resistance to chloroquine spread quickly through most areas with endemic malaria and made the drug less effective at clearing the parasite.

Recent research at the Australian National University (ANU) and Germany’s University of Heidelberg has shown that the mutated parasite protein that causes resistance has an Achilles heel.

“We studied diverse versions of this protein and in all cases found that it is limited in its capacity to remove the drug from the parasite,” said Dr Rowena Martin, a researcher at the ANU Research School of Biology.

“This means malaria could once again be treated with chloroquine if it is administered twice daily, rather than just once a day.”

Chloroquine is still used in developing nations in the South Pacific, Africa, Asia and South America, but has been withdrawn from use in many developed countries.

Dr Martin and colleagues also revealed how the protein may have developed resistance to chloroquine.

“We found that the protein gains the ability to move chloroquine out of the parasite through one of two evolutionary pathways, but that this process is rigid - one wrong turn and the protein is rendered useless,” she said.

“This indicates that the protein is under conflicting pressures, which is a weakness that could be exploited in future antimalarial strategies.”

Dr Martin said that there is also potential to apply the findings to several chloroquine-like drugs that are also becoming less effective as the malaria parasite builds up resistance. However, she does not recommend taking large doses of chloroquine.

“The key is to increase the frequency of chloroquine administration; for example, by taking a standard dose in the morning and another at night. If you take too much all at once it can kill you,” she cautioned.

The study was published in Proceedings of the National Academy of Sciences USA