The findings could revive the use of the cheap anti-malarial drug chloroquine in treating and preventing the mosquito-borne disease, which claims the lives of more than half a million people each year around the world.
The parasite that causes malaria has developed resistance to chloroquine, but research carried out at the Australian National University (ANU) and Germany's University of Heidelberg has shown that the 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 malaria researcher Dr Rowena Martin, from 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," said Martin.
Once hailed as a wonder drug, chloroquine is still used in developing nations in the South Pacific, Africa, Asia and South America, but has been withdrawn from use in many developed countries.
Martin and her 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," said Martin.
Martin said the findings could be used to help millions of people in developing nations who are at risk of catching malaria.
She 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.
The study was published in the journal PNAS.