The Plasmodium parasites that cause malaria often develop resistance to antimalarial drugs. But according to a new Science study, parasites with mutations that make them resistant to an antimalarial called atovaquone can’t pass their resistance on to their offspring: The drug disrupts the lifecycles of the parasites while they’re living within their mosquito hosts.
Around 3.2 billion people are at risk for malaria, according to the World Health Organization. That’s almost half of the world’s population. Introduced in 2000, atovaquone, a component of the antimalarial medication Malarone, kills both the blood and liver stages of malaria. However, it’s prone to resistance, and researchers assumed that this resistance would spread – just as it has with other antimalarials.
To investigate, a team led by University of Melbourne’s Christopher Goodman and Geoffrey McFadden examined three atovaquone-resistant strains of Plasmodium berghei, a malarial parasite that infects rodents. Each strain contains a different mutation in their cytochrome b (cytB) gene, which is encoded in their mitochondrial DNA. The team let Anopheles stephensi mosquitoes feed on mice infected with the resistant Plasmodium strains, and then they followed the parasites over the course of their entire lifecycle – much of which happens inside of mosquito vectors.
While resistance mutations protected the parasites from the drug, these proved to be lethal later on in the mosquito phase. Two of the mutations resulted in developmental defects in the parasites’ fertilized embryos, and the third mutation led to complete infertility. The team describes cytB mutations as "genetic time bombs."
Because maternally-inherited mitochondrial DNA is critical for a molecular process that Plasmodium rely on when they’re living inside of mosquitoes, the resistant parasites weren’t able to respire efficiently. Since this severely impairs their reproductive cells, atovaquone-resistant mutations can’t be passed on to the next generation of parasites.
In a total of 44 separate transmission attempts – involving 750 mosquito bites – the transmission of atovaquone resistance was observed just once. And this mutation couldn’t be transmitted further, despite seven attempts. Cross breeding parasites with and without these mutations didn’t work either. "The cytB mutations in the mitochondrial DNA of atovaquone-resistant rodent malaria parasites render them effectively female sterile and hence largely unable to pass on the resistance gene," the team wrote.
While this study focused on the rodent parasite, the human malaria parasite Plasmodium falciparum has similar mutations that impair its ability to successfully infect mosquitoes. "We now understand the particular genetic mutation that gave rise to drug resistance in some malaria parasite populations and how it eventually kills them in the mosquito, providing new targets for the development of drugs," McFadden said in a statement.
Next, the team plans to look for the spread of drug resistance in the field in Kenya and Zambia.