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Malaria Parasite Sequences Highlight Drug Resistance Mutations, Potential Treatment Targets

NEW YORK (GenomeWeb) – A University of California, San Diego-led team has tallied up drug resistance mechanisms — and started searching for new treatment targets — in the Plasmodium falciparum malaria parasite.

After spurring parasite evolution and drug resistance through exposure to a series of anti-malarial drugs and new candidate inhibitor compounds, the researchers did whole-genome sequencing on more than 200 drug-resistant P. falciparum clones. Their analyses of these and other drug-resistant malaria parasite sequences pointed to hundreds of amplifications and non-synonymous mutations, falling in 83 genes, leading to resistance to more than three dozen compounds.

As the team reported today in Science, the resistance mechanisms at play included drug target changes not identified in the past. But the drug-resistant P. falciparum parasite sequence set is also expected to help in designing future treatments that malaria parasites might be less adept at dodging.

"Our findings showed and underscored the challenging complexity of evolved drug resistance in P. falciparum, but they also identified new drug targets or resistance genes for every compound for which resistant parasites were generated," senior author Elizabeth Winzeler, a pharmacology and drug discovery researcher at UCSD, said in a statement.

Malaria parasites are notorious for their ability to dodge host immune responses and anti-malarial treatments, the team explained, in part because the nature of malaria infections provide conditions that allow for parasite evolution.

"A single human infection can result in a person containing upwards of a trillion asexual blood stage parasites," Winzeler explained. "Even with a relatively slow random mutation rate, these numbers confer extraordinary adaptability."

After prompting in vitro parasite evolution over several months in an initially isogenic P. falciparum clone using a collection of growth inhibitors, the researchers did whole-genome sequencing on 204 drug-resistant P. falciparum clones evolved to dodge the effects of 37 different compounds, including 26 drugs with demonstrated anti-malarial effects.

The team analyzed the parasite genomes alongside 58 published sequences, representing parasites resistant to a dozen drugs, to narrow in on more than 1,900 SNPs and small insertions or deletions in the core P. falciparum genome and beyond. In the core genome, resistance appeared to stem from 148 non-synonymous mutations and 159 copy number variants — including several gene amplifications — affecting 83 parasite genes.

As expected, known resistance and drug response genes were over-represented in that gene set, the researchers reported, noting that 35 of the genes had two or more apparent ties to resistance in the analysis. In addition, resistance alleles typically clustered for P. falciparum parasites exposed to drugs with comparable chemical structures.

The team took a closer look at these resistance genes, identifying new and known resistance mechanisms. By bringing in protein structure data, metabolomic profiles, and other information, the group used the mutation information from the resistant clones to search for new drug target candidates.

"This exploration of the P. falciparum resistome — the collection of antibiotic resistance genes — and its druggable genome will help guide new drug discovery efforts and advance our understanding of how the malaria parasite evolves to fight back," Winzeler said.

In a related perspectives article in Science, New York University researcher Jane Carlton wrote that the "rich data set" established by Winzeler and her colleagues "increases our understanding of the biology and evolution of P. falciparum, providing a powerful contribution toward basic research for malaria elimination.

Carlton called it "imperative" to find new parasite inhibitors to control malaria, as P. falciparum "is now resistant to most drugs that have been developed." She also noted that "designing 'resistance-proof' drugs may be the best strategy for controlling malaria," but cautioned that despite advances in this direction, "the field has some way to mature."

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