Resistance
Since the first documentation of P. falciparum chlorquine resistance in the 1950s, resistant strains have appeared throughout East and West Africa, Southeast Asia, and South America. The effectiveness of chloroquine against P. falciparum has declined as resistant strains of the parasite evolved. They effectively neutralize the drug via a mechanism that drains chloroquine away from the digestive vacuole. Chloroquine-resistant cells efflux chloroquine at 40 times the rate of chloroquine-sensitive cells; the related mutations trace back to transmembrane proteins of the digestive vacuole, including sets of critical mutations in the PfCRT gene (Plasmodium falciparum chloroquine resistance transporter). The mutated protein, but not the wild-type transporter, transports chloroquine when expressed in Xenopus oocytes and is thought to mediate chloroquine leak from its site of action in the digestive vacuole. Resistant parasites also frequently have mutated products of the ABC transporter PfMDR1 gene (Plasmodium falciparum multidrug resistance gene) although these mutations are thought to be of secondary importance compared to Pfcrt. Verapamil, a Ca2+ channel blocker, has been found to restore both the chloroquine concentration ability and sensitivity to this drug. Recently, an altered chloroquine-transporter protein CG2 of the parasite has been related to chloroquine resistance, but other mechanisms of resistance also appear to be involved.
Research on the mechanism of chloroquine and how the parasite has acquired chloroquine resistance is still ongoing, other mechanisms of resistance are likely.
Read more about this topic: Chloroquine
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