Abstract
Despite several setbacks in the fight against malaria such as insecticide and drug resistance as well as low efficacy of available vaccines, considerable success in reducing malaria burden has been achieved in the past decade. Artemisinins (ARTs and their combination therapies, ACTs), the current frontline drugs against uncomplicated malaria, rapidly kill plasmodial parasites and are non-toxic at short exposures. Though the exact mode of action remains unclear, the endoperoxide bridge, indispensable for ART activity, is thought to react with heme released from hemoglobin hydrolysis and generate free radicals that alkylate multiple protein targets, thereby disrupting proteostasis pathways. However, rapid development of ART resistance in recent years with no potential alternatives on the horizon threaten the elimination efforts. The Greater Mekong Subregion in South-East Asia continues to churn out mutants resistant to multiple ACTs and detected in increasingly expanding geographies. Extensive research on ART-resistant strains have identified a potential candidate Kelch13, crucial for mediating ART resistance. Parasites with mutations in the propeller domains of Plasmodium falciparum Kelch13 protein were shown to have enhanced phosphatidylinositol 3-kinase levels that were concomitant with delayed parasite clearance. Current research focused on understanding the mechanism of Kelch13-mediated ART resistance could provide better insights into Plasmodium resistome. This review covers the current proposed mechanisms of ART activity, resistance strategies adopted by the parasite in response to ACTs and possible future approaches to mitigate the spread of resistance from South-East Asia.
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Acknowledgements
We thank CSIR for providing fellowship assistance to Mr. Rahul Pasupureddy (09-905(0013)2013-EMRI). Special thanks to National Institute of Malaria Research (NIMR), New Delhi, for providing basic infrastructural facilities.
Funding
This work was supported by the Council of Scientific and Industrial Research (CSIR), Govt. of India (37(1630)/14/EMRII) and Department of Science and Technology (DST), Govt. of India (SB/SO/BB/0092/2013).
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Section Editor: Tobili Sam-Yellowe
The original version of this article was revised as author Atul Yadav would like to present his name as Atul only to be the same with his previous publications.
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Pasupureddy, R., Atul, Seshadri, S. et al. Current scenario and future strategies to fight artemisinin resistance. Parasitol Res 118, 29–42 (2019). https://doi.org/10.1007/s00436-018-6126-x
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DOI: https://doi.org/10.1007/s00436-018-6126-x