Abstract
Life has a prodigious capacity to overcome death, and this is exactly emblematic of drug resistance, one of the biggest threats for health systems, clinicians, researchers and patients. Several decades of intense and innovative drug discovery and development were not able to prevent the loss of medicines owing to resistance among viruses, bacteria and parasites. The common denominator to drug resistance is the ability of the targeted microorganisms to select the very few of them that can overcome the selective pressure and grow, often as a result of mutations occurring in genes coding for either drug targets, drug transporters and efflux pumps, or drug degradation systems. In the context of malaria, even the latest generation of drugs, such as the artemisinins that were not supposed to act through a unique target and thus able to resist resistance mechanisms, has started to lose their full efficacy in patients. In wild‐type parasites, the endoperoxide bond of artemisinin and its derivatives is cleaved in the presence of haem‐Fe2+ liberated from proteolyzed haemoglobin. Two processes have been described; the first generates oxygen radicals, which, via hydrogen atom abstraction or β‐scission processes, lead to carbon‐based radicals that can form covalent bonds with proteins and lipids in close vicinity. The second process involves a two‐electron heterolytic cleavage, in which the peroxide's oxidation potential causes death of the parasite (Haynes et al , 2013). The resulting alkylations or oxidative stress become extremely toxic to the parasite and inactivate vital functions. The cleavage of endoperoxides occurs mainly in the parasite's trophozoite blood stage where haemoglobin proteolysis takes place, and in very young ring stages, which makes artemisinins and all endoperoxides fast‐acting molecules. Most of the endoperoxides, with the exception of the ozonide OZ439, are short‐lasting molecules. Once activated, artemisinins and endoperoxides kill parasites very fast, making them extremely …
Highlights
L ife has a prodigious capacity to overcome death, and this is exactly emblematic of drug resistance, one of the biggest threats for health systems, clinicians, researchers and patients
Artemisinin combination therapies (ACTs) failed in patients in Cambodia owing to drug resistance
The mechanism of resistance is caused by mutations in the gene encoding Kelch13, a protein domain that is involved in sensing intracellular oxidative stress following reactions of artemisinins and potentially other endoperoxides
Summary
L ife has a prodigious capacity to overcome death, and this is exactly emblematic of drug resistance, one of the biggest threats for health systems, clinicians, researchers and patients. Since the mid-1980s, artemisinins and artemisinin-derived molecules have been used in combination therapy with partner drugs so as to avoid the development and spread of drug resistance. Artemisinin combination therapies (ACTs) failed in patients in Cambodia owing to drug resistance.
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
