Cookies on this website

We use cookies to ensure that we give you the best experience on our website. If you click 'Accept all cookies' we'll assume that you are happy to receive all cookies and you won't see this message again. If you click 'Reject all non-essential cookies' only necessary cookies providing core functionality such as security, network management, and accessibility will be enabled. Click 'Find out more' for information on how to change your cookie settings.

Artemisinin derivatives and their partner drugs in artemisinin combination therapies (ACTs) have played a pivotal role in global malaria mortality reduction during the last two decades. The loss of artemisinin efficacy due to evolving drug-resistant parasites could become a serious global health threat. Dihydroartemisinin-piperaquine is a well tolerated and generally highly effective ACT. The implementation of a partner drug in ACTs is critical in the control of emerging artemisinin resistance. Even though artemisinin is highly effective in parasite clearance, it is labile in the human body. A partner drug is necessary for killing the remaining parasites when the pulses of artemisinin have ceased. A population of Plasmodium falciparum parasites in Cambodia and adjacent countries has become resistant to piperaquine. Increased copy number of the genes encoding the haemoglobinases Plasmepsin II and Plasmepsin III has been linked with piperaquine resistance by genome-wide association studies and in clinical trials, leading to the use of increased plasmepsin II/plasmepsin III copy number as a molecular marker for piperaquine resistance. Here we demonstrate that overexpression of plasmepsin II and plasmepsin III in the 3D7 genetic background failed to change the susceptibility of P. falciparum to artemisinin, chloroquine and piperaquine by both a standard dose-response analysis and a piperaquine survival assay. Whilst plasmepsin copy number polymorphism is currently implemented as a molecular surveillance resistance marker, further studies to discover the molecular basis of piperaquine resistance and potential epistatic interactions are needed.

Original publication

DOI

10.1016/j.ijpddr.2018.11.004

Type

Journal article

Journal

International journal for parasitology. Drugs and drug resistance

Publication Date

04/2019

Volume

9

Pages

16 - 22

Addresses

Genomics and Evolutionary Medicine Unit (GEM), Centre of Excellence in Malaria Research, Faculty of Tropical Medicine, Mahidol University, Bangkok, 10400, Thailand; Molecular Medicine Program, Multidisciplinary Unit, Faculty of Science, Mahidol University, Bangkok, 10400, Thailand.

Keywords

Plasmodium falciparum, Quinolines, Chloroquine, Protozoan Proteins, Antimalarials, Microbial Sensitivity Tests, Inhibitory Concentration 50, Drug Resistance, Gene Dosage, Cambodia, Aspartic Acid Endopeptidases, Artesunate