Known genetic determinants of naturally occurring resistance mechanisms. Mutations (red dot) of the dihydrofolate reductase (PfDHFR) enzyme prevent its inhibition by the antifolate drugs pyrimethamine (PYR) and cycloguanil (CYC). Similarly, sulphadoxine (SDX) resistance is mediated by mutations of its target dihydropteroate synthetase (PfDHPS). Atovaquone (ATO) binds to the cytochrome bc1 complex (PfCYTB), mutations of which have been shown to induce high level of ATO resistance. Chloroquine (CHQ) is believed to prevent haeme detoxification within the digestive vacuole. Mutations of the CHQ resistance transporter (PfCRT) as well as of the multidrug resistance protein-1 (PfMDR1), including copy number variations, have been shown to compromise CHQ action by preventing its accumulation within the digestive vacuole. Mutations of these two transporters have also been implicated with mefloquine resistance, although definite marker has not been established for this drug.