Table 1.

Origins of resistance in malaria parasite, Plasmodium falciparum, to monotherapy drugs.

Monotherapy application dates	Drug and its mechanism	Resistance and its mechanism
∼1930–1950	Chloroquine interferes with the detoxification of heme by accumulating in the digestive vacuole of Plasmodium (Haldar et al., 2018).	∼1950. Mutations in transporter genes enabling efflux of chloroquine: chloroquine resistance transporter (PfCRT) (Martin et al., 2009) (Haldar et al., 2018); chloroquine transporter (CG2) (Haldar et al., 2018); ABC transporter (PfMDR1) (Haldar et al., 2018).
1953	Pyrimethamine and sulfadoxine inhibit folate pathway (Gregson and Plowe, 2005; Hyde, 2005) by blocking dihydropteroate synthase (PfDhps) and dihydrofolate reductase (PfDhfr).	2009 (Gesase et al., 2009). Mutations in and/or amplification of PfDhps and PfDhfr genes (Shah et al., 2011; Costa et al., 2017).
∼1960	Piperaquine interferes with the detoxification of heme by accumulating in the digestive vacuole of Plasmodium (Eastman and Fidock, 2009).	2010 (Duru et al., 2016). Amplification of parasite protease genes, such as plasmepsin 2 and 3 (Haldar et al., 2018).
1972	Artemisinin suggested to interfere with the detoxification of heme (Eastman and Fidock, 2009).	2008 (Dondorp et al., 2009). Mutations in transporter genes, such as PfK13, enabling efflux of Chloroquine; or a change in target recognized by the parasite (Ouji et al., 2018).