Multidrug-resistant (MDR) Plasmodium falciparum is partially responsible for the global resurgence of malaria. With the failing of many antimalarial drugs, most malaria-endemic countries have changed to artemisinin-based combination therapies (ACTs). Although ACT is highly effective, recent detection of reduced sensitivity in P. falciparum to artemisinins in several regions of Southeast Asia has raised great concerns. Although early resistance detection is essential for deterring and containing resistance, current detection of artemisinin resistance relies exclusively on clinical observations and in vitro drug assays. The lack of understanding of the exact mode of action and the mechanism of resistance for artemisinins makes resistance surveillance in areas of artemisinin deployment very difficult. To address this urgent problem, we have selected Thailand, China's Yunnan and Myanmar as our strategic sites to investigate artemisinin resistance. Southeast Asia has been the epicenter of drug resistant malaria parasites. The prevalence of MDR parasites, extensive deployment of artemisinins often as monotherapy, and the detection of reduced susceptibility to artemisinins among parasite populations suggest that artemisinin resistance is likely to arise in this region. In this study, we propose to 1) systematically sample P. falciparum clinical isolates and accurately determine their in vitro sensitivity to a panel of antimalarial drugs including artemisinins;2) determine the correlations of artemisinin-resistance with polymorphisms in the genome using both candidate gene and genome-wide association study (GWAS) approaches;3) validate promising mutations within candidate genes through allelic exchange experiments;and 4) develop molecular methods for detecting the mutation(s) responsible for artemisinin resistance and perform field surveillance of the resistance marker(s). The integration of a comprehensive sampling scheme, accurate in vitro drug assays and GWAS will provide essential information for elucidating the mechanism of artemisinin resistance, understanding how artemisinin resistance evolves, and facilitating the design of molecular methods to closely monitor resistance development in areas of ACT deployment.

Public Health Relevance

Artemisinin is currently our last line of defense against multi-drug resistant malaria parasites. Here we propose to determine the potential mechanism of artemisinin resistance in malaria parasites through systematic sampling of clinical samples in Southeast Asian regions where artemisinin resistance is likely to emerge, in vitro drug assays, and molecular association studies

National Institute of Health (NIH)
National Institute of Allergy and Infectious Diseases (NIAID)
Research Program--Cooperative Agreements (U19)
Project #
Application #
Study Section
Special Emphasis Panel (ZAI1-AWA-M)
Project Start
Project End
Budget Start
Budget End
Support Year
Fiscal Year
Total Cost
Indirect Cost
Pennsylvania State University
University Park
United States
Zip Code
Bunditvorapoom, Duangkamon; Kochakarn, Theerarat; Kotanan, Namfon et al. (2018) Fitness Loss under Amino Acid Starvation in Artemisinin-Resistant Plasmodium falciparum Isolates from Cambodia. Sci Rep 8:12622
Siddiqui, Faiza A; Cabrera, Mynthia; Wang, Meilian et al. (2018) Plasmodium falciparum Falcipain-2a Polymorphisms in Southeast Asia and Their Association With Artemisinin Resistance. J Infect Dis 218:434-442
Yang, Henglin; Wang, Jingyan; Liu, Hui et al. (2018) Randomized, Double-Blind, Placebo-Controlled Studies to Assess Safety and Prophylactic Efficacy of Naphthoquine-Azithromycin Combination for Malaria Prophylaxis in Southeast Asia. Antimicrob Agents Chemother 62:
Chaverra-Rodriguez, Duverney; Macias, Vanessa M; Hughes, Grant L et al. (2018) Targeted delivery of CRISPR-Cas9 ribonucleoprotein into arthropod ovaries for heritable germline gene editing. Nat Commun 9:3008
Mbenda, Huguette Gaelle Ngassa; Zeng, Weilin; Bai, Yao et al. (2018) Genetic diversity of the Plasmodium vivax phosphatidylinositol 3-kinase gene in two regions of the China-Myanmar border. Infect Genet Evol 61:45-52
Bai, Yao; Zhang, Jiaqi; Geng, Jinting et al. (2018) Longitudinal surveillance of drug resistance in Plasmodium falciparum isolates from the China-Myanmar border reveals persistent circulation of multidrug resistant parasites. Int J Parasitol Drugs Drug Resist 8:320-328
Zhao, Yan; Zeng, Jie; Zhao, Yonghong et al. (2018) Risk factors for asymptomatic malaria infections from seasonal cross-sectional surveys along the China-Myanmar border. Malar J 17:247
Deng, Zeshuai; Li, Qing; Yi, Haoan et al. (2018) Hemoglobin E protects against acute Plasmodium vivax infections in a Kachin population at the China-Myanmar border. J Infect 77:435-439
Zhong, Daibin; Koepfli, Cristian; Cui, Liwang et al. (2018) Molecular approaches to determine the multiplicity of Plasmodium infections. Malar J 17:172
Zhu, Xiaotong; He, Yang; Liang, Yifan et al. (2017) Tryptophan-rich domains of Plasmodium falciparum SURFIN4.2 and Plasmodium vivax PvSTP2 interact with membrane skeleton of red blood cell. Malar J 16:121

Showing the most recent 10 out of 115 publications