Southeast Asia has been the hotbed for the development of drug-resistant malaria parasites, including those with resistance to artemisinin combination therapy. While mutations in the kelch propeller domain (K13 mutations) are associated with artemisinin resistance, a range of evidence suggests that other factors are critical for the establishment and subsequent transmission of resistance in the field. Here, we perform a quantitative analysis of DNA damage and repair in the malaria parasite Plasmodium falciparum and find a strong link between enhanced DNA damage repair and artemisinin resistance. This experimental observation is further supported when variations in seven known DNA repair genes are found in resistant parasites, with six of these mutations being associated with K13 mutations. Our data provide important insights on confounding factors that are important for the establishment and spread of artemisinin resistance and may explain why resistance has not yet arisen in Africa.
School of Biological Sciences, Nanyang Technological University, 60 Nanyang Dr., Singapore 637551, Singapore; BioSystems and Micromechanics (BioSyM) Interdisciplinary Research Group (IRG), Singapore-MIT Alliance for Research and Technology (SMART), 1 Create Way, Singapore 138602; Antimicrobial Resistance (AMR) IRG, Singapore-MIT Alliance for Research and Technology (SMART), 1 Create Way, Singapore 138602, Singapore.
Humans, Plasmodium falciparum, DNA Damage, Artemisinins, Protozoan Proteins, DNA Repair, Life Cycle Stages, Drug Resistance, Genotype, Phenotype, Geography, Africa, Asia, Southeastern, Protein Domains