Chloroquine resistance in the malarial parasite, Plasmodium falciparum

Malarial parasites remain a health problem of staggering proportions. Worldwide, they infect about 500 million, incapacitate tens of millions, and kill approximately 2.5 million (mostly children) annually. Four species infect humans, but most deaths are caused by one particular species, Plasmodium falciparum. The rising number of malarial deaths is due in part to increased drug resistance in P. falciparum. There are many varieties of antimalarial drug resistance, and there may very well be several molecular level contributions to each variety. This is because there are a number of different drugs with different mechanisms of action in use, and more than one molecular event may sometimes be relevant for resistance to any one class of drugs. Thus, "multidrug" resistance in a clinical setting likely entails complex combinations of overlapping resistance pathways, each specific for one class of drug, that then add together to confer the particular multidrug resistance phenotype. Nonetheless, rapid progress has been made in recent years in elucidating mechanisms of resistance to specific classes of antimalarial drugs. As one example, resistance to the antimalarial drug chloroquine, which has been the mainstay therapy for decades, is becoming well understood. This article focuses on recent advances in determining the molecular mechanism of chloroquine resistance, with particular attention to the biochemistry and biophysics of the P. falciparum digestive vacuole, wherein changes in pH have recently been found to be associated with chloroquine resistance.