Bacterial pathogens aren't the only ones that can evolve to evade the drugs we throw at them. In southeast Asia, Plasmodium falciparum, the parasite that causes malaria, has begun to develop resistance to a drug called artemisin.

Artemisin has been the front-line drug used against malaria since the 1990s, when malaria became resistant to the previous drugs used to combat it. Currently, no real alternatives exist. Combating malaria is a pretty serious priority, as it kills a child a minute in Africa. If we lose our most potent weapon against it, that combat will become much more difficult.

(Artemisin's name comes from its source, sweet wormwood—Artemisia annua—which is related, but not identical, to the wormwood used to make absinthe, Artemisia absinthium.)

Understanding resistance is challenging because it is not really clear how artemisin works—which parasitic proteins or processes it disrupts. While genome-wide association studies have identified mutations in resistant strains of the parasite, it has been difficult to figure out how these mutations might interfere with the drug. New work has now shown how these mutations are able to cause resistance; results are reported in Nature.

Artemisin binds to and thereby blocks the activity of a parasitic enzyme called PfPI3K, so you'd expect that to be critical. But no mutations were found in PfPI3K in any artemisin-resistant strains of malaria. Instead, the most prevalent mutation in resistant populations was in a protein called PfKelch13. Currently, we don't know the function of this protein, just that it does not interact with artemisin.

The mammalian protein that is most similar to PfKelch13 is involved in protein degradation, so the researchers thought that PfKelch13 might be as well. They were right. PfKelch13 plays a role in delivering artemisin's target, PfPI3K, to the cellular protein degradation machinery. The mutations in PfKelch13 that cause artemisin resistance do so by preventing it from degrading artemisin's target, PfPI3K.

As a result, resistant strains have about twice as much PfPI3K in them than sensitive strains do; artemisin can't inhibit all of that extra enzyme. This twofold increase in PfPI3K levels was able to increase resistance by a factor of 10, though, suggesting that its effects are amplified by its downstream targets.

It is tempting to speculate that upping the dose of artemisin might solve this problem, although a study that doubled the dose from 4mg/kg/day to 8 did not find that to be the case. It might be difficult to increase it further because of toxicity issues. Perhaps other inhibitors of PfPI3K can be discovered, and perhaps drugs might be found to inhibit PfKelch13.

Nature, 2015. DOI: 10.1038/nature14412, 10.1038/nature14387.

Clin Infect Dis, 2013. DOI: 10.1093/cid/cis958 (About DOIs).