Mutant malaria parasites resistant to antimalarial Atovaquone cannot spread: new research

Scientists found that malaria parasites resistant to antimalarial Atovaquone cannot survive inside their mosquito host. Anest/www.shutterstock.com

Resistance to a commonly used antimalarial medication, Atovaquone, can’t spread to the general human population, new research suggests.

This is significant as scientists have been racing against malaria parasites’ rapid resistance to various antimalarial medications.

Resistance to antimalarial drugs hinders effective treatment of malaria, a life-threatening mosquito-borne infectious disease of which almost half of the world’s population (3.2 billion) are at risk of contracting.

An international team of researchers led by scientists from Eijkman Institute and University of Melbourne published the research today in Science.

The research shows that Atovaquone, a component of an effective antimalarial drug Malarone, interrupts the life cycle of resistant parasites in the mosquito phase.

“Drug resistance will not spread [to other patients] because mosquitoes will not be able to spread [the resistant strain]. This shows that Atovaquone is a safe drug,” co-principal investigator of the research, Professor Sangkot Marzuki, molecular biologist at the Eijkman Institute for molecular biology in Jakarta said.

Senior research officer from the Burnett Institute Paul Gilson, who was not involved in the research, said the findings show an “important breakthough” in malaria treatment.

“The big picture is that Atovaquone, once thought of as a second rate drug because parasites can easily become resistant to it, might be extremely effective at stopping malaria transmission and could therefore be important for disease eradication,” he said.

Like other antimalarials, Atovaquone is prone to resistance. The research findings debunked the assumption that resistance to Atovaquone will spread as it has with other antimalarials such as Artemisinin.

Commenting on the research, James McCarthy, professor of infectious diseases at Queensland Institute of Medical Research, who was not involved in the study said: “this suggests that the drug may be very useful in helping stop the spread of Artemisinin resistant parasites”.

“This [the research] would allow us to think about using Atovaquone to try to stop Artemisinin-resistant parasites from spreading because they would still be sensitive to Atovaquone,” Co-principal investigator Professor Geoffrey McFadden from University of Melbourne said.

Currently, Artemisinin-resistant malaria parasites have been discovered in the greater Mekong Delta and Indonesia. “If it gets away from there it then could become global,” Professor McFadden said.

Professor Marzuki said the findings are “important for future research on drug development” to treat not only malaria but also other parasitic diseases.

Malaria parasites have two life cycles: first, in their mammalian hosts, such as mice or humans; second, in their mosquito hosts.

The research shows that some malaria parasites developed a genetic mutation that protected them against Atovaquone in early life inside their mammalian hosts. But the mutation eventually killed the parasites in the mosquito life phase by stopping production of an essential type of energy as they grew.

Professor McFadden called it a “genetic trap”.

The research shows that Atovaquone can stop the life cycle of the resistant parasites, stopping them from spreading in the field, because it targets a protein called cytochrome b.

This protein, located inside the parasite’s cell – specifically in the mitochondria – is essential for the cells of the parasite to breath and release energy.

“The research shows that the target molecule of the drug is very important for the survival of the parasite in mosquitoes,” Professors Marzuki said. “Therefore, it’s a good target for future drug development for malaria and other parasitic diseases,” he added.

Professor Marzuki said using mice models, the team of researchers looked into how the parasites mutate inside their mammalian hosts and become resistant to the drug. The researchers isolated resistant mutants by periodically exposing parasites that are infecting mice with dosages of Atovaquone that would not kill the parasites entirely.

Malaria parasite. Courtesy of University of Melbourne

Professor Marzuki said the resistant parasites show mutations in their mitochondrial-DNA that expresses the gene for cytochrome b.

Professor Marzuki said this mutant strain survives in the mammalian host perhaps because even though cytochrome b could not function well in this strain, malaria parasites only need low respiratory activity when living in the red blood cells.

The researchers then tested the transmissibility of the resistant strain. They observed whether mice that had been bitten by mosquitoes that had bitten mice infected by the resistant strain will be infected too. The tests show the mosquitoes could not transmit the resistant strain to other mice.