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Chloroquine: molecular basis of resistance
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6.10.08
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The molecular basis of resistance is still not fully understood. Resistance to chloroquine is said to be due to a reduced accumulation of the product in the lysosome of the parasite. In vitro this is reversible with verapamil. On chromosome 7 of the parasite is the gene pfcrt which codes for the protein PfCRT (Plasmodium falciparum chloroquine resistance tranporter). This is a transmembrane protein in the digestive vacuole. The protein facilitates the transport of positively loaded organic cations (efflux of protonated amino acids). Resistant mutants have a reduced efficiency of this amino acid transport, so that more H+-ions remain in the lysosome, which becomes more acid. The mutated protein has an increased affinity for chloroquine, so that these molecules are pumped out of the digestive vacuole. The roles of other mutations, e.g. pgh1 and pfmdr (P. falciparum multidrug-resistance transporter) for example, have not yet been fully clarified.
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