Chloroquine: A Hypothesis Concerning Plasmodium falciparum Resistance Mechanisms

Abstract

Pharmacological studies suggest that chloroquine resistance is associated with drug decreased intracellular concentration below biologically effective levels.Three different mechanisms have been considered: (i) an increased lysosomal pH would reduce chloroquine acidotropic accumulation; (ii) a rapid efflux mechanism; and (iii) decreased chloroquine cell intake. However, biochemical, molecular and genetic studies have produced ambiguous results concerning the molecular mechanism. Two candidates have been identified. The first one is the pfmdrl gene, having mutations which seem to be associated with chloroquine resistance. However, several experiments suggest that this gene's mutations do not confer resistance by themselves. The other candidate is the cg2 gene; this has tandem repeat regions, having specific polymorphisms which have been correlated with chloroquine resistance in Asia and Africa. Additionally, a recent study proposed a model consistent with a resistance factor acting in the food vacuole where CG2 is located, thus strengthening the hypothesis that this protein plays an important role in resistance development. More research is still required to elucidate the chloroquine resistance mechanism or mechanisms.