Chloroquine Resistance In Malaria Parasites Research Articles

Detection of Plasmodium falciparum chloroquine resistance transporter (PfCRT) mutant gene amongst malaria-infected pregnant women in Calabar, Nigeria

Chemotherapy is the mainstay in malaria control and management. For some time, chloroquine (CQ) was a drug of choice for the treatment of malaria. It was effective against all forms of malaria, cheap and readily available. The increased resistance of malaria parasites to CQ led to widespread abandonment of the drug in African and Asian countries on the prompting of the World Health Organization. Currently, artemisinin-based combination therapy is the gold standard for the treatment of malaria. This study investigates the presence of the Plasmodium falciparum Chloroquine Resistance Transporter (PfCRT) mutant gene, a molecular marker responsible for CQ resistance in malaria parasites. A total of 369 pregnant women were microscopically screened for malaria infection using thin and thick blood films stained with Giemsa. Subsequently, malaria parasite DNA was extracted from the blood of malaria positive participants. The PfCRT gene was amplified using Polymerase Chain Reaction (PCR). A Restriction Fragment Length Polymorphism analysis of the gene was performed to confirm mutant forms. The results showed that 251 (68.0%) of the participants had Plasmodium falciparum in their blood. Molecular examination revealed the presence of PfCRT mutant genes in 28% of the study population. Notwithstanding the decline in the prevalence of PfCRT T76 mutation since the antimalarial policy change in Nigeria, the 28% prevalence recorded in this study is considered high after ten years of the withdrawal of CQ in the treatment of uncomplicated malaria.

Simultaneous administration of 2-aminoethyl diphenylborinate and chloroquine reverses chloroquine resistance in malaria parasites.

A nearly complete reversal of chloroquine (CQ) resistance in the CQ-resistant Plasmodium falciparum K-1 strain, with a significant decrease in the mean ± standard deviation (SD) 50% inhibitory concentration (IC50) from 1,050 ± 95 nM to 14 ± 2 nM, was achieved in vitro by the simultaneous administration of 2-aminoethyl diphenylborinate (2-APB). The CQ resistance-reversing activity of 2-APB, which showed the same efficacy as verapamil, was also observed in an in vivo mouse infection model with the CQ-resistant Plasmodium chabaudi AS(30CQ) strain.

Plasmodium falciparum chloroquine resistance marker protein (Pfcrmp) may be a chloroquine target protein in nucleus

We previously hypothesized that the key site of chloroquine (CQ) antimalarial action and resistance development is in nucleus of malaria parasite, and that lysosomal (food vacuolar) accumulation of CQ may benefit parasite's survival through reducing the drug pressure on the key site. To further support our hypothesis we propose that Plasmodium falciparum chloroquine resistance marker protein (Pfcrmp) may be a CQ target protein in nucleus and that CQ resistance in malaria parasites may be caused by genetic alterations in Pfcrmp gene.

The malaria parasite's chloroquine resistance transporter is a member of the drug/metabolite transporter superfamily.

The malaria parasite's chloroquine resistance transporter (CRT) is an integral membrane protein localized to the parasite's acidic digestive vacuole. The function of CRT is not known and the protein was originally described as a transporter simply because it possesses 10 transmembrane domains. In wild-type (chloroquine-sensitive) parasites, chloroquine accumulates to high concentrations within the digestive vacuole and it is through interactions in this compartment that it exerts its antimalarial effect. Mutations in CRT can cause a decreased intravacuolar concentration of chloroquine and thereby confer chloroquine resistance. However, the mechanism by which they do so is not understood. In this paper we present the results of a detailed bioinformatic analysis that reveals that CRT is a member of a previously undefined family of proteins, falling within the drug/metabolite transporter superfamily. Comparisons between CRT and other members of the superfamily provide insight into the possible role of the protein and into the significance of the mutations associated with the chloroquine resistance phenotype. The protein is predicted to function as a dimer and to be oriented with its termini in the parasite cytosol. The key chloroquine-resistance-conferring mutation (K76T) is localized in a region of the protein implicated in substrate selectivity. The mutation is predicted to alter the selectivity of the protein such that it is able to transport the cationic (protonated) form of chloroquine down its steep concentration gradient, out of the acidic vacuole, and therefore away from its site of action.

Parasitology. A requiem for chloroquine.

The arrival of chloroquine resistance in malaria parasites ended the reign of the best and most affordable antimalarial drug ever. The resurgence of malaria in developing countries, particularly in sub-Saharan Africa, is nothing short of a humanitarian disaster. In this Perspective, Hastings and colleagues explore new findings (Sidhuet al.) that reveal how chloroquine resistance evolved. The new work may shed light on appropriate antimalarial drug combinations that do not exhibit cross-resistance, in this way delaying the emergence of resistance to new frontline drugs.

Chloroquine resistance in plasmodium falciparum is not reversed by BIBW-22, a compound reversing the multidrug resistance phenotype in mammalian cancer cells

The pteridine derivative BIBW-22 (4-[N-(2-hydroxy-2-methyl-propyl)-ethanolamino]-2,7-bis( cis-2,6-dimethyl-morpholino)-6-phenylpteridine), which had been developed for the treatment of multidrug-resistant cancer and binds to P-glycoprotein, was tested against chloroquine resistant Plasmodium falciparum strains in culture. Based on the result that BIBW-22 enhanced rather than lowered chloroquine resistance in vitro, it is concluded that chloroquine resistance in malaria parasites may not be mechanistically linked to the multidrug-resistant phenotype of chloroquine resistant P. falciparum.

Genetics of chloroquine resistance in malaria parasites.

THE resistance of the malaria parasite of man, Plasmodium falciparum, to treatment with chloroquine is a growing problem, especially in South-east Asia and South America1. It is not known whether the emergence of resistance is attributable to the selection of resistant mutants under drug pressure, to the spread of naturally resistant forms in the parasite population or to adaptation to the drug by previously sensitive parasites. In malaria parasites of rodents, it has been shown that resistance to the antifolate drug pyrimethamine arises by mutation2 and that the genetic factors involved can undergo recombination with other markers in crosses between resistant and sensitive parasite lines3. Resistance to chloroquine in rodent plasmodia seems to take several forms. P. yoelii isolates are innately resistant to the drug4, whereas P. berghei and P. vinckei are sensitive. Stable chloroquine resistance has been produced in P. vinckei by drug selection in the laboratory5 but resistance developed in this way in P. berghei is usually unstable in the absence of the drug6.