Last year, there were over 200 million cases of malaria, and they resulted in nearly half a million deaths. Efforts to control the disease have had limited success. The mosquitos that carry it have rapidly evolved resistance to insecticides like DDT, and there are now areas of the globe where the parasite that causes the disease are resistant to even our most effective treatment.

Efforts to develop new drugs are challenging. The malarial parasite, Plasmodium, is a eukaryote like us, and thus it shares a lot of basic biochemistry. That makes it harder to find a drug that targets the parasite but not human cells. Plasmodium also has a complex life cycle, with stages that are rather distinct. That makes generating vaccines difficult, and it ensures some treatments only work on a subset of these stages.

But new approaches to screening drugs have turned up a number of promising leads in recent years. One success, reported this week in Nature, involves a drug that targets a Plasmodium protein that no other drug works on. In tests on mice, the drug was able to clear an infection with a single dose.

The report comes from a huge international collaboration with the scale to match: the team screened approximately 100,000 new chemicals for activity against malaria. These weren't just any chemicals, either; instead, they were specifically designed to adopt three-dimensional structures that are similar to those of known biomolecules. The idea is that this would make it more likely that the chemicals tested could stick to a protein by occupying a site that the protein normally uses to interact with a chemical found inside cells. Ideally, the binding of the drug would disrupt the normal activity of the protein.

Each of the drugs was tested for its ability to slow down parasite growth in cultured red blood cells. Four different sets of related chemicals came out of the screen. Three of them bound to proteins that are already targets of known drugs. So, while they could end up being useful, they're not anything new.

The fourth chemical, however, was something entirely new, and nobody knew what it was sticking to. The structure of the chemical doesn't provide many clues, given it's got a large series of rings, some of them with unusual numbers of carbon atoms. So to figure out how it worked, the team intentionally used low doses of the drug for a few months to allow Plasmodium to evolve resistance to it. Once the parasite survived the drug, they sequenced its genome, looking for changes that could be associated with the resistance.

The gene they came up with encodes a protein that helps attach amino acids to RNA, a step that's essential for getting them incorporated into proteins. In this case, the protein helped attach phenylalanine to RNA; phenylalanine is an amino acid with a ring structure, which may explain how the drug could interfere with its metabolism.

The problem with the drug as it was originally isolated was that it didn't dissolve well in water. So the team tested a number of derivatives, one of which was much more water soluble. When this drug was given to mice, its half-life in the blood was 36 hours—enough time for a single dose to persist for several days.

This revised chemical was also tested in mice, which didn't complain of any side effects (nor were there any indication of any). A single dose of the drug was able to completely clear any sign of infection from the mice. It was also effective when ingested orally. The drug appeared to work against several different stages of the parasite's life cycle as well, clearing infections from both the blood and the liver. Given its effectiveness, the authors also suggest that it could help limit the spread of the parasite back to mosquitos.

But the main thing the researchers are excited about is the single dose. Malaria, including the drug-resistant varieties, is most prevalent in areas where the medical facilities are sparse or nonexistent. Getting people in those areas to successfully complete a course of treatment is a real challenge—one where failure encourages the evolution of drug resistance. Being able to clear the parasite with a single dose could solve that problem.

Obviously, there's still a lot of human testing that will be needed. But with results this promising, that testing is almost certainly to be in the works.

Nature, 2016. DOI: 10.1038/nature19804 (About DOIs).