Malaria's drug-resistance genes found

How the malaria parasite develops resistance to certain anti-malarial drugs has been uncovered thanks to DNA sequencing.

Malaria kills half a million people a year and is spread by mosquitoes which transmit the disease when they feed. The Plasmodium parasite passes into the victim in saliva regurgitated by the insect when it bites. In Cambodia, Plasmodiun strains are showing resistance to the frontline drug piperaquine, making current treatments useless.

Now a new study, published in The Lancet Infectious Diseases, has sequenced the genomes of 297 Plasmodium strains recovered from infected Cambodian patients.  This DNA data was used to identify genes which grant piperaquine protection and also how resistant strains of the bug are spreading across the country.

"You have a simple tool you can use to monitor how far resistance has gotten and deploy, at the regional level, the best treatment," says the study's lead author Roberto Amato of the Wellcome Trust's Sanger Institute in Cambridgeshire.

To identify resistance genes, scientists first recorded how successful piperaquine was at removing parasites from the patient.

The parasite genomes were then read to see if there was a genetic difference between parasites that were sensitive to piperaquine and those that were not.

The researchers found one DNA change, or "mutation", which causes drug treatment to fail 60% of the time.  Without this mutation, the therapy had only a 5% failure rate.

The mutation was a duplication of two genes known as Plasmepsin II and Plasmepsin III; resistance was conferred by having at least two copies of these genes, although some parasites had up to five copies of one of the genes.

The Plasmepsin genes help the parasite eat.  Malaria lives inside human red blood cells and uses haemoglobin, the protein which carries oxygen around the body, for food.  The Plasmepsin genes encode proteins that can digest haemoglobin.

Piperaquine works by blocking haemoglobin breakdown. But multiple copies of the Plasmepsin genes can allow the parasite to devour haemoglobin faster, surmounting the action of the drug.

In the future, once malarial infections have been identified as having the genes for piperaquine resistance, other treatments can be substituted instead. 

"The good news is that we observed that parasites that are resistant to piperaquine are also, at the molecular level, sensitive to a drug we have used in the past which is mefloquine," explains Amato.

Resistant parasites spread rapidly from one area to another because they cannot be killed by drugs. They multiply quickly in an infected person. Mosquitoes then take up the resistant parasites when feeding and transmit them to other people wherein the cycle repeats. Resistance to a previous antimalarial, chloroquine, first emerged in Southeast Asia before spreading to Africa. It caused millions of deaths because the drug became ineffective.

In the future, patients suffering from malaria, or another infection, may have their parasite's genomes sequenced before being treated so they are given the right drugs.