scholarly journals In search of a selective inhibitor of the induced transport of small solutes in Plasmodium falciparum-infected erythrocytes: effects of arylaminobenzoates

1995 ◽  
Vol 311 (3) ◽  
pp. 761-768 ◽  
Author(s):  
K Kirk ◽  
H A Horner
Keyword(s):  
Plasmodium Falciparum ◽  
Mammalian Cells ◽  
High Capacity ◽  
Transport Systems ◽  
Single Type ◽  
Transport Pathway ◽  
Choline Transport ◽  
Pharmacological Agents ◽  
Diverse Range

Following invasion of the human erythrocyte by the malaria parasite, Plasmodium falciparum, there appear in the parasitized cell new, high-capacity permeation pathways that transport a diverse range of low-molecular-mass solutes. In this study a series of 16 arylaminobenzoates, analogues of the Cl- channel blocker 5-nitro-2-(3-phenylpropylamino)benzoic acid (NPPB), were tested for their effects on the transport of choline, a univalent cation, into malaria-infected cells. A number of the arylaminobenzoates were found to be potent inhibitors of malaria-induced choline transport and to be similarly effective at blocking the induced transport of the uncharged pyrimidine nucleoside thymidine and the univalent anion lactate. The data are consistent with the hypothesis that much of the induced transport of cations, anions and non-electrolytes into parasitized cells is via broad-specificity, anion-selective pathways of a single type. A comparison of the effects of the arylaminobenzoates on malaria-induced transport with their effects on a number of representative anion transport systems in normal mammalian cells suggests that it is possible to identify pharmacological agents that block the malaria-induced pathway while not significantly affecting important transport mechanisms in host tissues. The most potent of the induced-transport inhibitors identified were shown to inhibit [3H]hypoxanthine incorporation in in vitro parasite growth assays. These data support the view that the induced-transport pathway may be a viable pharmacological target.

scholarly journals Enhanced choline and Rb+ transport in human erythrocytes infected with the malaria parasite Plasmodium falciparum

1991 ◽  
Vol 278 (2) ◽  
pp. 521-525 ◽  
Author(s):  
K Kirk ◽  
H Y Wong ◽  
B C Elford ◽  
C I Newbold ◽  
J C Ellory
Keyword(s):  
Plasmodium Falciparum ◽  
Malaria Parasite ◽  
Human Erythrocytes ◽  
Transport Pathway ◽  
Choline Transport ◽  
Transport Component ◽  
Parasite Plasmodium ◽  
Parasite Plasmodium Falciparum ◽  
Infected Cells

Human erythrocytes infected in vitro with the malaria parasite Plasmodium falciparum showed a markedly increased rate of choline influx compared with normal cells. Choline transport into uninfected cells (cultured in parallel with infected cells) obeyed Michaelis-Menten kinetics (Km approximately 11 microM). In malaria-parasite-infected cells there was an additional choline-transport component which failed to saturate at extracellular concentrations of up to 500 microM. This component was less sensitive than the endogenous transporter to inhibition by the Cinchona bark alkaloids quinine, quinidine, cinchonine and cinchonidine, but showed a much greater sensitivity than the native system to inhibition by piperine. The sensitivity of the induced choline transport to these reagents was similar to that of the malaria-induced (ouabain- and bumetanide-resistant) Rb(+)-transport pathway; however, the relative magnitudes of the piperine-sensitive choline and Rb+ fluxes in malaria-parasite-infected cells varied between cultures. This suggests either that the enhanced transport of the two cations was via functionally distinct (albeit pharmacologically similar) pathways, or that the transport was mediated by a pathway with variable substrate selectivity.

scholarly journals Reversal of Mefloquine and Quinine Resistance in Plasmodium falciparum with NP30

2003 ◽  
Vol 47 (8) ◽  
pp. 2393-2396 ◽  
Author(s):  
Michelle Ciach ◽  
Kathleen Zong ◽  
Kevin C. Kain ◽  
Ian Crandall
Keyword(s):  
Plasmodium Falciparum ◽  
Multidrug Resistance ◽  
Genetic Analysis ◽  
Resistance Genes ◽  
Mammalian Cells ◽  
Point Mutations ◽  
In Vitro Assays ◽  
Drug Efflux ◽  
P Glycoprotein

ABSTRACT Quinoline resistance in malaria is frequently compared with P-glycoprotein-mediated multidrug resistance (mdr) in mammalian cells. We have previously reported that nonylphenolethoxylates, such as NP30, are potential Plasmodium falciparum P-glycoprotein substrates and drug efflux inhibitors. We used in vitro assays to compare the ability of verapamil and NP30 to sensitize two parasite isolates to four quinolines: chloroquine (CQ), mefloquine (MF), quinine (QN), and quinidine (QD). NP30 was able to sensitize (reversal, >80%) P. falciparum to MF, QN, QD, and, to a lesser extent, CQ. The presence of 2 μM verapamil had no effect on mefloquine resistance; however, the presence of verapamil modulated the activities of QN and QD in a manner parallel to that observed for CQ. Genetic analysis of putative quinoline resistance genes did not suggest an association between known point mutations in pfcrt and pfmdr1 and NP30 sensitization activity. We conclude that the sensitization action of NP30 is distinct both phenotypically and genotypically from that of verapamil.

scholarly journals Increased choline transport in erythrocytes from mice infected with the malaria parasite Plasmodium vinckei vinckei

1998 ◽  
Vol 334 (3) ◽  
pp. 525-530 ◽  
Author(s):  
Henry M. STAINES ◽  
Kiaran KIRK
Keyword(s):  
Malaria Parasite ◽  
Significant Contribution ◽  
Transport Pathway ◽  
Choline Transport ◽  
Parasite Plasmodium ◽  
Broad Specificity ◽  
Plasmodium Vinckei ◽  
Rule Out

Parasitized erythrocytes from mice infected with the murine malaria parasite Plasmodium vinckei vinckei showed a marked increase in the rate of influx of choline compared with erythrocytes from uninfected mice. In contrast, uninfected erythrocytes from P. vinckei-infected animals transported choline at the same rate as those from uninfected mice. The increased influx of choline into parasitized cells was via two discrete routes. One was a saturable pathway with a Km similar to that of the choline carrier of normal erythrocytes but a Vmax approx. 20-fold higher than that observed in uninfected cells. The other was a non-saturable pathway inhibited by furosemide. At choline concentrations within the normal physiological plasma concentration range, the former pathway contributed approx. two-thirds and the latter approx. one-third of the influx of choline into parasitized cells. The characteristics of the furosemide-sensitive pathway were similar to those of a broad-specificity pathway that is induced in human erythrocytes infected in vitro with Plasmodium falciparum. The results of this study rule out the possibility that the induced transport pathway of P. falciparum-infected erythrocytes is an artifact arising in vitro from the long-term culture of parasitized cells and provide evidence that this pathway makes a significant contribution to the uptake of choline into the parasitized cells of malaria-infected animals.

scholarly journals Effects of Synthetic Siderophores on Proliferation of Plasmodium falciparum in Infected Human Erythrocytes

2002 ◽  
Vol 46 (6) ◽  
pp. 2010-2013 ◽  
Author(s):  
Andrea Rotheneder ◽  
Gernot Fritsche ◽  
Lothar Heinisch ◽  
Ute Möllmann ◽  
Susanne Heggemann ◽  
...  
Keyword(s):  
Plasmodium Falciparum ◽  
Mammalian Cells ◽  
Human Erythrocytes ◽  
Lethal Doses

ABSTRACT Because iron is essential for Plasmodium falciparum, we investigated the in vitro potential of various synthetic siderophores to kill P. falciparum in infected human erythrocytes. The substances with the most promising profile, i.e., low 50% lethal doses for plasmodia and minimum toxicity towards mammalian cells, were siderophores with an acylated monocatecholate or a triscatecholate as substituent.

scholarly journals Potent and Selective Activity of a Combination of Thymidine and 1843U89, a Folate-Based Thymidylate Synthase Inhibitor, against Plasmodium falciparum

2000 ◽  
Vol 44 (4) ◽  
pp. 1047-1050 ◽  
Author(s):  
Lei Jiang ◽  
Pei-Chieh Lee ◽  
John White ◽  
Pradipsinh K. Rathod
Keyword(s):  
Plasmodium Falciparum ◽  
Thymidylate Synthase ◽  
Mammalian Cells ◽  
De Novo ◽  
Antimalarial Activity ◽  
Malarial Parasite ◽  
Drug Resistant ◽  
Additional Tool ◽  
Synthase Inhibitor

ABSTRACT Unlike mammalian cells, malarial parasites are completely dependent on the de novo pyrimidine pathway and lack the enzymes to salvage preformed pyrimidines. In the present study, first, it is shown that 1843U89, even without polyglutamylation, is a potent folate-based inhibitor of purified malarial parasite thymidylate synthase. The binding was noncompetitive with respect to methylenetetrahydrofolate, and 1843U89 had a Ki of 1 nM. The compound also had potent antimalarial activity in vitro. Plasmodium falciparum cells in culture were inhibited by 1843U89, with a 50% inhibitory concentration of about 70 nM. The compound was effective against drug-sensitive as well as drug-resistant clones ofP. falciparum. As predicted by the biochemistry of the parasite, the potent inhibition of parasite proliferation by 1843U89 could not be reversed with 10 μM thymidine. In contrast, in the presence of 10 μM thymidine, mammalian cells were unaffected by 1843U89 even at concentrations as high as 0.1 mM, thus offering a selectivity window of more than 1,000-fold. On this basis, folate-based thymidylate synthase inhibitors may represent a powerful additional tool that can be used to combat drug-resistant malaria.

scholarly journals Hybrid Gold(I) NHC-Artemether Complexes to Target Falciparum Malaria Parasites

Molecules ◽  
2020 ◽  
Vol 25 (12) ◽  
pp. 2817
Author(s):  
Manel Ouji ◽  
Guillaume Barnoin ◽  
Álvaro Fernández Álvarez ◽  
Jean-Michel Augereau ◽  
Catherine Hemmert ◽  
...  
Keyword(s):  
Public Health ◽  
Plasmodium Falciparum ◽  
Mammalian Cells ◽  
Antimalarial Drugs ◽  
Cross Resistance ◽  
Major Threat ◽  
Hybrid Molecules ◽  
Low Cytotoxicity ◽  
Nanomolar Range

The emergence of Plasmodium falciparum parasites, responsible for malaria disease, resistant to antiplasmodial drugs including the artemisinins, represents a major threat to public health. Therefore, the development of new antimalarial drugs or combinations is urgently required. In this context, several hybrid molecules combining a dihydroartemisinin derivative and gold(I) N-heterocyclic carbene (NHC) complexes have been synthesized based on the different modes of action of the two compounds. The antiplasmodial activity of these molecules was assessed in vitro as well as their cytotoxicity against mammalian cells. All the hybrid molecules tested showed efficacy against P. falciparum, in a nanomolar range for the most active, associated with a low cytotoxicity. However, cross-resistance between artemisinin and these hybrid molecules was evidenced. These results underline a fear about the risk of cross-resistance between artemisinins and new antimalarial drugs based on an endoperoxide part. This study thus raises concerns about the use of such molecules in future therapeutic malaria policies.

scholarly journals Frequency of drug resistance in Plasmodium falciparum: a nonsynergistic combination of 5-fluoroorotate and atovaquone suppresses in vitro resistance.

1996 ◽  
Vol 40 (4) ◽  
pp. 914-919 ◽  
Author(s):  
S Gassis ◽  
P K Rathod
Keyword(s):  
Drug Resistance ◽  
Plasmodium Falciparum ◽  
Mammalian Cells ◽  
Cross Resistance ◽  
Synergistic Activity ◽  
Individual Resistance ◽  
In Vitro Method ◽  
Proof Of Principle

A combination of 5-fluoroorotate and atovaquone eliminated Plasmodium falciparum in long-term cultures more efficiently than either compound alone. The improved potency came not through synergistic activity but through decreased frequency of drug resistance. In support of this finding, it was shown that 5-fluoroorotate and atovaquone do not act in a synergistic fashion, that 5-fluoroorotate-resistant and atovaquone-resistant P. falciparum organisms generated in vitro do not show cross-resistance, and that the frequency of simultaneous resistance to the two compounds approached the product of their individual resistance frequencies. To demonstrate the last finding, and establish proof of principle, an in vitro method was developed for measuring the frequency of drug resistance in P. falciparum. By this method, it was shown that the frequency of resistance to 10(-7) M 5-fluoroorotate was about 10(-6) and the frequency of resistance to 10(-8) M atovaquone was about 10(-5); the frequency of simultaneous resistance to a combination of 10(-7) M 5-fluoroorotate and 10(-8) M atovaquone was less than 5 x 10(-10). On the basis of additional measurements, it was estimated that the frequency of simultaneous resistance to higher, pharmacologically more relevant, concentrations of 10(-6) M 5-fluoroorotate and 10(-7) M atovaquone would be less than 10(-17). Control experiments demonstrated that these drug combinations did not cause increased toxicity to mammalian cells in culture. On this basis, it is predicted that a combination of 5-fluoroorotate and atovaquone will successfully eliminate typical malarial infections in animals and in human patients at doses that are readily tolerated.

scholarly journals Differential in vitro activities of ionophore compounds against Plasmodium falciparum and mammalian cells.

1996 ◽  
Vol 40 (3) ◽  
pp. 602-608 ◽  
Author(s):  
C Gumila ◽  
M L Ancelin ◽  
G Jeminet ◽  
A M Delort ◽  
G Miquel ◽  
...  
Keyword(s):  
Plasmodium Falciparum ◽  
Cell Lines ◽  
Mammalian Cells ◽  
Inhibitory Concentration ◽  
Antimalarial Activity ◽  
Monovalent Cations ◽  
Macrophage Cell ◽  
Mammalian Cell Lines ◽  
Gramicidin D

Twenty-two ionophore compounds were screened for their antimalarial activities. They consisted of true ionophores (mobile carriers) and channel-forming quasi-ionophores with different ionic specificities. Eleven of the compounds were found to be extremely efficient inhibitors of Plasmodium falciparum growth in vitro, with 50% inhibitory concentrations of less than 10 ng/ml. Gramicidin D was the most active compound tested, with 50% inhibitory concentration of 0.035 ng/ml. Compounds with identical ionic specificities generally had similar levels of antimalarial activity, and ionophores specific to monovalent cations were the most active. Compounds were further tested to determine their in vitro toxicities against mammalian lymphoblast and macrophage cell lines. Nine of the 22 compounds, i.e., alborixin, lonomycin, nigericin, narasin, monensin and its methylated derivative, lasalocid and its bromo derivative, and gramicidin D, most specific to monovalent cations, were at least 35-fold more active in vitro against P. falciparum than against the two other mammalian cell lines. The enhanced ability to penetrate the erythrocyte membrane after infection could be a factor that determines ionophore selectivity for infected erythrocytes.

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