Experimental malaria drug may be a hot prospect

Parasite doesn’t develop resistance to synthetic compound in early tests

An experimental drug zaps the malaria parasite at multiple stages of infection, tests in mice show. And it may have an important upside: it doesn’t appear prone to drug resistance, the Achilles’ heel of malaria medicines.

While preliminary, the findings offer welcome news in a field beset by uneven performance as the malaria protozoa subvert drug after drug. The situation has gotten so bad that the World Health Organization now recommends that doctors prescribe two drugs at once to increase the odds of killing the parasite without allowing a resistant form to emerge.

In the face of this gloomy picture, authors of the new study are decidedly optimistic. “We do hope this is a game changer,” says biochemist Michael Riscoe of Oregon Health & Science University in Portland.  The report appears in the March 20 Science Translational Medicine.

Other scientists inject a note of caution. “No matter how good the drug looks at this point, most likely the parasite will figure out how to become resistant to it,” says Roland Cooper, a pharmacologist at Dominican University of California, in San Rafael. “The parasite is just a clever beast.”

But the experimental drug could still offer patients a benefit, he says. Since the drug candidate takes a long time to break down, it might last long enough in the body to clear infections. What’s more, the multipronged attack is unusual for malaria drugs. “It’s just exciting to have a drug look this good,” he says.  

Riscoe and his colleagues tested hundreds of compounds to find ones that combat malaria parasites, including Plasmodium falciparum, the species responsible for the most severe form of the illness. The novel drug candidate dubbed ELQ-300 showed a strong antimalarial effect against multidrug-resistant strains of P. falciparum and P. vivax malaria obtained from the blood of patients on the island of New Guinea.

ELQ-300 targets the parasite’s mitochondrion, the intracellular factory that supplies energy for a cell. In the single-celled parasite, the mitochondrion is also instrumental in manufacturing DNA building blocks, which are essential for survival. Lab tests showed that ELQ-300 sabotages the activity of mitochondrial proteins.

One currently used drug, atovaquone, also binds to mitochondrial proteins. But the malaria parasite has developed a genetic mutation that hinders this binding, says study coauthor Roman Manetsch, a chemist at the University of South Florida in Tampa. To test for resistance to the new drug candidate, the scientists exposed P. falciparum in the lab to atovaquone or ELQ-300 and checked whether the parasite survived in culture over eight weeks. As the scientists expected, some parasites exposed to atovaquone survived after becoming resistant. However, none survived ELQ-300 exposure.

People get malaria from the bite of an infected mosquito. The parasite goes through three broad stages once inside a human: one in the liver and then, in the bloodstream, an active stage that causes symptoms and a reproductive stage that can be transmitted via mosquitoes to others.

When tested in malaria-infected mice, ELQ-300 looks like a triple threat, hitting the parasite at each of these life stages. Like many antimalarials, ELQ-300 bested the parasite in the bloodstreams of the mice. But the experimental drug also stopped it in the liver. Parasites lodged in the liver can reemerge later, Manetsch says. “If you don’t clean out the whole host, there might be enough left to start a new infection.” These data are particularly heartening, Cooper says, because few drugs can do this.  

Another experiment showed that the drug kills the parasite in its reproductive stage in mosquitoes that had eaten a blood meal containing ELQ-300. The malaria protozoa reside in the female mosquito for a week or two, Riscoe says — so if the mosquito draws blood during this time from people who have ELQ-300 in their system, the drug should kill the parasites inside the bug, rendering it unable to infect people.

The drug candidate “has potential for malaria control,” Cooper says. “Not only would you do yourself a favor by taking it, you’d be doing your neighbor a favor.”

If the experimental drug passes more safety tests, Riscoe expects early trials in people in a couple of years.

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