Malaria Drug Resistance Is Becoming Increasingly Complex in Ethiopia

Microorganisms can evolve at extraordinary speed, giving them an advantage in a world where microbes prey on other microbes.

As soon as one organism develops a defence, another can evolve a means of bypassing or defeating it. Scientists call this an evolutionary arms race, one of nature's most potent evolutionary forces.

This formidable capacity for rapid evolution becomes a human problem when microbes direct it against the medicines used to treat life-threatening infections.

For the most pernicious malaria pathogen, moreover, drug resistance appears to be growing alarmingly complex.

A new genetic analysis of Plasmodium falciparum - the parasite behind the deadliest form of malaria - suggests it is accumulating adaptations associated with resistance to a broad range of drug treatments.

"These findings underscore the dual challenge of persistent resistance to discontinued drugs and rising threats to current frontline therapies," write infectious-disease researchers led by Alemayehu Letebo of Ethiopia's Armauer Hansen Research Institute, Leen N. Vanheer of the London School of Hygiene and Tropical Medicine in the UK, and colleagues.

Their work is described in Nature Microbiology.

[Video: accompanying YouTube video]

Malaria and the evolutionary arms race

Malaria ranks among the deadliest infectious diseases in the world. It infects hundreds of millions annually and kills hundreds of thousands, predominantly children under 5 and predominantly people in Africa.

Although the disease can be prevented and cured, researchers must continually race to remain ahead of the parasite. Over the past 70 years, P. falciparum has acquired resistance to nearly every antimalarial treatment developed, including artemisinin, one of the most important malaria medicines and a drug discovered in the 1970s.

Partial resistance to artemisinin was first detected in South-East Asia over 15 years ago, and has since been reported at several sites in Africa.

Yet resistance is not a straightforward on-off switch, appearing abruptly and disappearing once it is no longer useful.

Instead, it may involve numerous genetic alterations. Some arise in response to medicines now being used, whereas others may persist as leftovers from battles against drugs that have been retired.

A map showing where the samples were collected, malaria intensity, and malaria parasite overlap. (Letebo et al., Nat. Microbiol. 2026)

Ethiopia's P. falciparum drug-resistance landscape

The situation in Ethiopia is particularly intricate. Chloroquine ceased to work against P. falciparum long ago. The current first-line therapy is the artemether-lumefantrine combination, pairing an artemisinin medicine called artemether with lumefantrine.

However, P. falciparum is not malaria's only causative parasite. [P. vivax](https://en.wikipedia.org/wiki/Plasmodium_vivax), which generally causes a less fatal form of malaria, remains vulnerable to chloroquine and circulates across many of the same areas as P. falciparum.

The team therefore asked whether these overlapping drug pressures are influencing P. falciparum evolution, and whether the parasite carries multiple resistance markers in potentially troubling combinations.

They sequenced drug-resistance genes in 605 P. falciparum samples gathered from 15 Ethiopian districts between 2019 and 2023. The locations varied in malaria intensity and in the degree of P. vivax overlap.

Graphs detailing the prevalence, geographic spread, and co-occurrence of the resistance mutations. (Letebo et al., Nat. Microbiol. 2026)

The results showed that chloroquine-resistance markers remain widespread in the parasite, despite chloroquine having been removed from the P. falciparum treatment toolkit decades ago. The drug's genetic resistance pattern occurred in 61.2 percent of 492 successfully classified samples.

The researchers think continued chloroquine use for P. vivax malaria could be helping resistance persist in P. falciparum. Geographic patterns are consistent with this explanation, although further research is required.

They also identified markers linked with resistance to sulfadoxine-pyrimethamine in 42.8 percent of 453 samples. These remain common even though the therapy has not been used for malaria in Ethiopia since 2005.

Meanwhile, markers of resistance to current treatments are spreading. The principal marker of partial artemisinin resistance was present in 10 percent of 572 samples.

Other markers were less frequent overall, but were often concentrated in particular regions. In one district, partial artemisinin resistance was as high as 48.6 percent.

Resistance markers occur together

Most worrying, however, was the tendency for these resistance markers to occur alongside one another. For instance, parasites carrying chloroquine-resistance markers had more than threefold greater odds of also carrying markers for partial artemisinin resistance.

A genetic pattern linked to reduced lumefantrine sensitivity was also detected in 93 percent of 483 classified samples.

This creates the prospect of a double blow from resistance. It is important, however, that the researchers examined genetic markers rather than whether artemether-lumefantrine itself is becoming less effective.

The clearest conclusion is that Ethiopia does not face one consistent drug-resistance issue. Rather, it has a mosaic of parasite populations with differing combinations of mutations.

Consequently, efforts to combat malaria and treatment resistance cannot rely on a blanket, one-size-fits-all strategy.

This does not indicate that Ethiopia's present approach to malaria has ceased to work. Still, the researchers say the findings should serve as a warning.

Related: Drug-Resistant Bacteria May Be Jumping Between Pets And Humans, Scientists Warn

The parasite is not following one predictable evolutionary route, and identical drug pressures may not influence it in the same manner everywhere.

Health officials now have an opportunity to adapt surveillance strategies more closely to malaria parasite drug resistance's shifting and complicated landscape.

"Taken together, Ethiopia's distinct P. falciparum cluster, marked geographic heterogeneity in resistance markers and correlation with species composition highlight the need for region-specific control strategies," the researchers write.

"Integrated surveillance systems that monitor both P. falciparum and P. vivax, coupled with whole-genome sequencing and longitudinal data linked to clinical outcomes, will be essential to track resistance evolution and guide tailored interventions."

The paper was published in Nature Microbiology.

This article was fact-checked and edited by Fiona MacDonald. While we take pride in our process, we are only human. If you spot an error, please let us know.