K13-Mediated Reduced Susceptibility to Artemisinin in Plasmodium falciparum Is Overlaid on a Trait of Enhanced DNA Damage Repair
Aoli Xiong,
Prem Prakash,
Xiaohong Gao,
Marvin Chew,
Ian Jun Jie Tay,
Charles J. Woodrow,
Bevin P. Engelward,
Jongyoon Han,
Peter R. Preiser
Affiliations
Aoli Xiong
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
Prem Prakash
School of Biological Sciences, Nanyang Technological University, 60 Nanyang Dr., Singapore 637551, Singapore
Xiaohong Gao
School of Biological Sciences, Nanyang Technological University, 60 Nanyang Dr., Singapore 637551, Singapore
Marvin Chew
School of Biological Sciences, Nanyang Technological University, 60 Nanyang Dr., Singapore 637551, Singapore; Antimicrobial Resistance (AMR) IRG, Singapore-MIT Alliance for Research and Technology (SMART), 1 Create Way, Singapore 138602, Singapore
Ian Jun Jie Tay
Department of Biological Engineering, Massachusetts Institute of Technology, 77 Massachusetts Avenue, Cambridge, MA 02139, USA
Charles J. Woodrow
Mahidol-Oxford Tropical Medicine Research Unit, Faculty of Tropical Medicine, Mahidol University, 420/6 Rajvithi Road, Tungphyathai, Bangkok 10400, Thailand
Bevin P. Engelward
Department of Biological Engineering, Massachusetts Institute of Technology, 77 Massachusetts Avenue, Cambridge, MA 02139, USA
Jongyoon Han
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; Department of Electrical Engineering and Computer Science, Massachusetts Institute of Technology, 50 Vassar St., Cambridge, MA 02142, USA; Department of Biological Engineering, Massachusetts Institute of Technology, 77 Massachusetts Avenue, Cambridge, MA 02139, USA
Peter R. Preiser
School of Biological Sciences, Nanyang Technological University, 60 Nanyang Dr., Singapore 637551, Singapore; Antimicrobial Resistance (AMR) IRG, Singapore-MIT Alliance for Research and Technology (SMART), 1 Create Way, Singapore 138602, Singapore; Corresponding author
Summary: 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.
