Efflux of chloroquine from Plasmodium falciparum: mechanism of chloroquine resistance Abstract Chloroquine-resistant Plasmodium falciparum accumulate significantly less chloroquine than susceptible parasites, and this is thought to be the basis of their resistance. However, the reason for the lower accumulation of chloroquine was unknown.
Full Answer
Is chloroquine resistance in Plasmodium falciparum caused by a drug efflux carrier?
Sanchez CP, Stein W, Lanzer M (2003) Trans stimulation provides evidence for a drug efflux carrier as the mechanism of chloroquine resistance in Plasmodium falciparum. Biochemistry 42: 9383–9394.
Is chloroquine permeable to Plasmodium membranes?
The only form of chloroquine for which the erythrocyte and the external plasmodium membranes are permeable is the un-protonated one and this implies that CQ concentrations are the same on the two sides of these membranes.
Which of the following is an efflux pump inhibitor?
Thus, thioridazine, Phe-Arg β-naphthylamide (PAβN) or the arylpiperazine NMP are some of the compounds categorized as efflux pump inhibitors.
What causes rapid chloroquine efflux in CQR parasites?
The rapid chloroquine efflux revealed by CQR parasites under zero-transconditions and in the presence of metabolic energy was causatively linked to the K76T polymorphism within PfCRT (Fig. 5). The Dd2 back-mutant N3D6 did not show this rapid efflux.
How did malaria become resistant to chloroquine?
Abstract. Resistance to chloroquine of malaria strains is known to be associated with a parasite protein named PfCRT, the mutated form of which is able to reduce chloroquine accumulation in the digestive vacuole of the pathogen.
What is the mechanism of resistance of chloroquine?
The major action of chloroquine is to inhibit the formation of hemozoin (Hz) from the heme released by the digestion of hemoglobin (Hb). The free heme then lyses membranes and leads to parasite death. Chloroquine resistance is due to a decreased accumulation of chloroquine in the food vacuole.
How do malaria parasites become resistant to drugs?
Resistance of malaria parasites arises from several factors, including overuse of antimalarial drugs for prophylaxis, inadequate or incomplete therapeutic treatments of active infections, a high level of parasite adaptability at the genetic and metabolic levels, and a massive proliferation rate that permits selected ...
What is effective in treating chloroquine-resistant strains of Plasmodium?
Conclusions. Based on data obtained in Aotus monkeys infected with CQ-resistant parasites, it can be concluded that the tetrandrine-CQ combination is effective against chloroquine-resistant falciparum malaria in Aotus monkeys.
Which is the most probable mechanism of Plasmodial resistance to chloroquine?
Resistance to chloroquine of malaria strains is known to be associated with a parasite protein named PfCRT, the mutated form of which is able to reduce chloroquine accumulation in the digestive vacuole of the pathogen.
How does chloroquine work in the body?
Chloroquine phosphate is used to prevent and treat malaria. It is also used to treat amebiasis. Chloroquine phosphate is in a class of drugs called antimalarials and amebicides. It works by killing the organisms that cause malaria and amebiasis.
Is malaria resistant to chloroquine?
Chloroquine-resistant P. falciparum first developed independently in three to four areas in Southeast Asia, Oceania, and South America in the late 1950s and early 1960s. Since then, chloroquine resistance has spread to nearly all areas of the world where falciparum malaria is transmitted.
How does drug resistance occur in parasites?
The factors that can explain the emergence of resistance are: Reduction of drug concentration within the parasite, either by decreasing drug uptake or by increasing efflux of the drug; inhibition of drug activation; inactivation of active drug; and gene amplification [70].
What is a drug-resistant malaria case how is it being managed?
In antimalarial chemotherapy, drug resistance is defined as "the ability of a parasite strain to survive and/or multiply despite the administration and absorption of a drug in doses equal to or higher than those usually recommended but within the limits of tolerance of the subject".
Which one of these combination is used in chloroquine-resistant malaria?
Treatment of chloroquine-resistant malaria using pyrimethamine in combination with berberine, tetracycline or cotrimoxazole.
What is the drug of choice for chloroquine-resistant malaria?
Artemisinin-based combination therapies (ACTs). This is usually the preferred treatment for chloroquine-resistant malaria. Examples include artemether-lumefantrine (Coartem) and artesunate-mefloquine.
Which combination is useful for the treatment of chloroquine-resistant uncomplicated falciparum malaria?
Artemisinin combination therapy (ACT) is recommended as first-line treatment for uncomplicated Plasmodium falciparum malaria, whereas chloroquine is still commonly used for the treatment of non-falciparum species (Plasmodium vivax, Plasmodium ovale and Plasmodium malariae).
What is the role of drug transporters in antimicrobial resistance?
Drug transporters also function beyond resistance such as those involved in stress response and virulence. There is an ever-growing understanding of drug transporters with respect to their classification, structure, transport mechanisms, regulation and inhibition. This chapter provides an overview of the characteristics and resistance contributions of drug transporters through various examples of clinical significance, with an emphasis on the transporters of the resistance-nodulation-cell division (RND) superfamily in Gram-negative bacteria. The development of clinically-suitable efflux pump inhibitors and novel pump-circumventing antimicrobial drugs continues to be a challenging task. Additionally, the clinical significance of drug transporters highlights the importance of prudent antimicrobial use for minimizing the emergence and spread of antimicrobial drug resistance.
What is active drug extrusion?
Active drug extrusion mediated by efflux transporters is a phenomenon widely observed in both prokaryotic and eukaryotic cells. This process makes a great contribution to intrinsic and acquired resistance in bacteria, fungi and parasites against a broad range of antimicrobial agents and can further interplay with other resistance mechanisms.
What is the role of PMF pumps in E. coli biofilm?
Therefore, PMF pumps are considered to have important roles in the biofilm formation of E. coli. Indeed, these pumps may contribute to biofilm formation via the export or import of some substances that are necessary for or harmful to biofilm formation.58. The Role of Efflux Pumps in Candida albicansBiofilms.
What are the mechanisms that cause antimicrobial resistance in biofilms?
Several mechanisms are reportedly responsible for the antimicrobial resistance in biofilm structures: (1) poor diffusion of antibiotics through the biofilm polysaccharide matrix, although some antibiotics are able to penetrate the matrix;10.
What are the properties of biofilms?
One of the main properties of biofilms is their capacity to be more resistant to antimicrobial agents than planktonic cells.
Is C. albicans resistant to fluconazole?
C. albicansbiofilms are resistant to the antifungal agent fluconazole. It has been estimated that biofilms are up to 4,000 times more resistant to fluconazole in comparison with planktonic cells.65,66Efflux pumps play an additive role in contributing to fluconazole resistance in early-phase biofilms.
Does MexAB-OprM contribute to antibiotic resistance?
It has been demonstrated that MexAB-OprM plays a role in the resistance of aztreonam, gentamicin, tetracycline and tobramycin in biofilm structures. However, both MexCD-OprJ and MexEF-OprN do not seem to contribute to antibiotic resistance in biofilms.30.
What is the role of PFCRT in chloroquine?
J1) PfCRT acts as a passive channel for CQ + (or CQ ++, or both). and thereby the outward flux of chloroquine across the vacuole membrane due to PfCRT, J PfCRT, only depends upon the difference in concentration on the two sides of the vacuolar membrane and on the membrane potential.
Which amino acids are involved in chloroquine resistance?
Two amino acids of PfCRT are known to be involved in chloroquine resistance, 163 and 76, and therefore expected to be involved in the transport mechanism. To verify whether this is indeed the case, we built a homology model of the protein.
Is chloroquine a carrier or channel?
Resistance to chloroquine of malaria strains is known to be associated with a parasite protein named PfCRT, the mutated form of which is able to reduce chloroquine accumulation in the digestive vacuole of the pathogen. Whether the protein mediates extrusion of the drug acting as a channel or as a carrier and which is the protonation state of its chloroquine substrate is the subject of a scientific debate. We present here an analytical approach that explores which combination of hypotheses on the mechanism of transport and the protonation state of chloroquine are consistent with available equilibrium experimental data. We show that the available experimental data are not, by themselves, sufficient to conclude whether the protein acts as a channel or as a transporter, which explains the origin of their different interpretation by different authors. Interestingly, though, each of the two models is only consistent with a subset of hypotheses on the protonation state of the transported molecule. The combination of these results with a sequence and structure analysis of PfCRT, which strongly suggests that the molecule is a carrier, indicates that the transported species is either or both the mono and di-protonated forms of chloroquine. We believe that our results, besides shedding light on the mechanism of chloroquine resistance in P. falciparum, have implications for the development of novel therapies against resistant malaria strains and demonstrate the usefulness of an approach combining systems biology strategies with structural bioinformatics and experimental data.
Is PFCRT a DME?
On one hand several authors [14], [16] assigned PfCRT to the drug/metabolite transporter (DMT) superfamily and, among the previously defined protein families, reported that PfCRT has the highest similarity with the drug/metabolite exporter (DME) family. On this basis, the authors concluded that PfCRT is likely to function as an exporter of metabolites in symport with H +.
Is chloroquine a weak base?
Chloroquine is a diprotic weak base and, at physiological pH (∼7.4), can be found in its un-protonated (CQ), mono-protonated (CQ +) and di-protonated (CQ ++) forms. The uncharged chloroquine is the only membrane permeable form of the molecule and it freely diffuses into the erythrocyte up to the DV.
Is chloroquine the best antimalarial?
In the last decades, due to its effectiveness and reasonable cost, chloroquine has represented the best and more widely used antimalarial drug. Unfortunately, within a decade of its introduction, P. falciparum parasite resistance to chloroquine was observed in most of the malaria-endemic countries.