Chloroquine Resistance in Plasmodium falciparum

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Electron micrograph of the Ebola Zaire virus. This was the first photo ever taken of the virus, on 10/13/1976. By Dr. F.A. Murphy, now at U.C. Davis, then at the CDC.

By Edna Kemboi

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Section 1

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Plasmodium falciparum life cycle

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Mechanism of Chloroquine resistance

Within the last few decades, chloroquine was considered the best and more widely used antimalarial drug due to its effectiveness and its reasonable cost. Unfortunately, theP. falciparum parasite developed resistance to chloroquine. These resistance was mostly observed in malaria-endemic countries.

In its erythrocyte stage, P. falciparum invades the white blood cells where it forms a lysosomal isolated compartment known as the digestive vacuole (DV). The parasite grows in the erythrocite by ingesting haemoglobin from the host cell cytosol and depositing it in the digestive vacuole. The protein is degraded in the DV to its component peptides and hemewhich is incorporated into the inert and harmless crystalline polymer hemozoin(1). Chloroquine is a diprotic weak base and at low physiological pH (~7.4), it can be found in its unprotonated form, CQ, monoprotonated from, CQ+ and diprotonated , CQ++ forms. The unchanrged chloroquine is membrane permeable and it freely diffuses into the erythrocyte and into the DV. Inside the DV, Chloroquine becomes protonated. Since the membrane is not permeable to any charged species, the chloroquine accumulates in the DV. Charged chloroquine is believed to bind to haematin, a toxic byproduct of the haemoglobin proteolysis which prevents its incorporation into the haemozoin crystal. Free haematin seems to interfere with the parasite detoxificationprocess therefore damaging the plasmodium membrane(1).

Chloroquine sensitive parasites accumulate more chloroquine in their DV than chloroquine resistant strains. Reduced chloroquine accumulation in the resistant parasite strains have been associated with the mutation in the gene encoding for plasmodium falciparum chloroquine resistant promoter (PfCRT). PfCRT is localized in the digestive vacuole and it is believed to aid in the exiting of positively charged chloroquine which decreases the concentration of chloroquine in the DV. It is however not clear if PfCRT acts as a carrier or a channel. The recent finding however suggests that PfCRT is an active carrier belonging to the family of Drug/Metabolite transporter superfamily (1).


[1] Chinappi M, Via A., Marctili P., and Tramontano A. "On the Mechanism of Chloroquine Resistance in Plasmodium falciparum." 2010. PLoS ONE 5(11): e14064. doi:10.1371/journal.pone.0014064.

Authored for BIOL 238 Microbiology, taught by Joan Slonczewski, 2015, Kenyon College.