Study identifies malaria resistance genes, possible drug targets

A new study of drug resistance in the parasite responsible for roughly half of all malaria cases worldwide has identified more than 80 genes that contribute to resistance, some of which could provide important information for drug development, researchers say.

In the study, published in Science, an international team of researchers grew clonal isolates of Plasmodium falciparum in the lab in the presence of 37 different small molecules with known antimalarial activity over the course of 3 to 6 months. The purpose of this experimental evolution was to study how drug resistance evolves in the parasite, which is known for its ability to rapidly adapt to evade antimalarial drugs and the human immune system.

After the isolates had developed resistance to the molecules, the researchers then conducted whole-genome sequencing on the 262 drug-resistant clones to identify the genetic basis of drug resistance. Sequencing of the "druggable genome" revealed 83 genes that likely contribute to drug resistance, with hundreds of variations within those genes, and one identified for each molecule tested.

Some of the genes had been previously identified, but several were new to the researchers. While the investigators believe many of these genes may contribute to clinical drug resistance at some level, some of the identified genes may also be potential targets for new antimalarial drugs.

"Our findings showed and underscored the challenging complexity of evolved drug resistance in P. falciparum," senior author Elizabeth Winzeler, PhD, a professor of pharmacology and drug discovery at University of California-San Diego (UCSD) School of Medicine, said in a UCSD press release. "But they also identified new drug targets or resistance genes for every compound for which resistant parasites were generated." 

'Major step forward'

An accompanying commentary by New York University microbiologist Jane Carlton, PhD, whose research focuses on malaria, notes that the study presents a "major step forward" in understanding the parasite and how to fight it. "This rich data set increases our understanding of the biology and evolution of P. falciparum, providing a powerful contribution toward basic research for malaria elimination," Carlton wrote.

According to the World Health Organization's (WHO's) most recent world malaria report, 216 million cases of malaria and 445,000 deaths were recorded in 2016. Although malaria is endemic in 91 countries and territories, more than 90% of malaria cases, and deaths, occur in sub-Saharan Africa. P falciparum and Plasmodium vivax are the primary causes of malaria in humans, but P falciparum is the deadlier of the two.

Because resistance to antimalarial drugs such as chloroquine and pyramethine is widespread, the current recommended treatment for malaria is an artemisinin-based combination therapy (ACT). Greater access to ACT, rapid diagnostic tests, and insectide-treated mosquito netting has helped reduce the malaria incidence rate by 18% globally since 2010, according to WHO data.

In recent years, however, a strain of P falciparum resistant to artemisinin and its partner drug piperaquine has begun to emerge in the countries of the Greater Mekong subregion—Cambodia, Laos, Myanmar, Thailand, and Vietnam. Global health officials worry that spread of this resistance could threaten progress against the disease.

See also:

Jan 12 Science study

Jan 11 UCSD press release

Jan 12 Science commentary

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