Protecting future antimalarials from the trap of resistance: Lessons from artemisinin-based combination therapy (ACT) failures.

Having faced increased clinical treatment failures with dihydroartemisinin-piperaquine (DHA-PPQ), Cambodia swapped the first line artemisinin-based combination therapy (ACT) from DHA-PPQ to artesunate-mefloquine given that parasites resistant to piperaquine are susceptible to mefloquine. However, triple mutants have now emerged, suggesting that drug rotations may not be adequate to keep resistance at bay. There is, therefore, an urgent need for alternative treatment strategies to tackle resistance and prevent its spread. A proper understanding of all contributors to artemisinin resistance may help us identify novel strategies to keep artemisinins effective until new drugs become available for their replacement. This review highlights the role of the key players in artemisinin resistance, the current strategies to deal with it and suggests ways of protecting future antimalarial drugs from bowing to resistance as their predecessors did. [Display omitted] • Molecular Mechanisms of Artemisinin action and Resistance. • Current Strategies for Combating ACT failures. • Profiles of the Antimalarial Drugs in Development. • Lessons learnt from ACT failures as guide for the development of future antimalarial drugs. • The ideal antimalarial Single Exposure Radical Cure and Prophylaxis (SERCaP). [ABSTRACT FROM AUTHOR]