Understanding resistance to antimalarial 4-aminoquinolines, cinchona alkaloids and the highly hydrophobic arylaminoalcohols

With the exception of Central America and the Caribbean, falciparum malaria resistant to the 4-aminoquinoline chloroquine is now found throughout the tropics. Using, allelic exchange, mutation K76T in lysosomal membrane protein PfCRT of the intraerythrocytic parasite has been proved to be responsible. An additional residue change (A220S) appears necessary but not sufficient. The effectiveness of more hydrophobic 4-aminoquinolines like desethylamodiaquine in chloroquine resistance in Africa is possibly associated with the more hydrophobic PfCRT 72CVIET76 haplotype, in contrast with SVMNT and CVMNT. Resistance to 4-aminoquinolines in the presence of modified PfCRT is enhanced by residue changes in another lysosomal membrane protein, PGH-1, a member of the multidrug-resistance associated 'ATP-binding cassette' (ABC) protein group. PGH-1 mediates resistance to arylaminoalcohols, like quinine and other cinchona alkaloids and to the highly hydrophobic arylaminoalcohols (HHAAs) such as mefloquine. In quinine resistance, PGH-1 residue-changes are similar to those seen in enhanced 4-aminoquinoline resistance. In contrast, increased copy number of wild-type PGH-1 is found in clinical resistance to the HHAA mefloquine. There is also evidence of some interaction between the arylaminoalcohols and PfCRT. In the case of quinine and its diastereomer quinidine, sterospecificity has been demonstrated. Although the main genetic determinants of resistance are now clear, there is some evidence for the involvement of other genes.