Scientists say they have found a new compound that stops malaria in animal studies with a single, low dose.
Tests in mice showed the one-off treatment prevented infection for the full 30 days of the study.
The chemical compound fought early infection in the liver, as well as malaria parasites that were circulating in the blood.
The researchers hope their early work, published in the journal, Nature, could lead to new drugs for people.
Malaria is spread to humans by the bites of infected female mosquitoes and it is estimated that about half of the world's population is at risk of catching the disease.
In 2015, there were 214 million new cases of malaria and 438,000 malaria deaths, according to the World Health Organization.
Aside from avoiding bites by using insecticides and bed nets, people can protect themselves against malaria by taking antimalarial drugs.
But existing treatments are less than perfect - people have to take repeated doses and the parasites that cause malaria are developing resistance to these drugs.
Need for new drugs
Along the Cambodia-Thailand border, one type of malaria parasite - P. falciparum - has become resistant to almost all available antimalarial medicines.
Dr Nobutaka Kato and colleagues, from Massachusetts Institute of Technology and Harvard, searched a library of more than 100,000 compounds for a new treatment.
They were hunting for something that would work in an entirely new way to existing drugs.
The compound they found targets an enzyme called phenylalanyl-tRNA synthetase and appears to wipe out parasites before they can multiply in the liver and be released in bigger numbers into the bloodstream.
Lead researcher Prof Stuart Schreiber hopes the findings will lead to the discovery of better antimalarials in coming years.
He said: "We invite the scientific community to use this database as a jumping off point for their work developing antimalarial therapies."
The work was funded by the Bill & Melinda Gates Foundation.
Prof David Baker of the London School of Hygiene & Tropical Medicine said the findings were exciting.
"The advantage of a single dose antimalarial is that it potentially reduces costs and removes the issue of patients not completing the course of treatment.
"One of the safety tests they ran on the new compounds gave results suggesting that there may be a degree of toxicity in human cells, but hopefully the chemists will be able to modify the compounds to remove this issue."