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PubMedDate not supplied

The efficacy of benzimidazole drugs against Plasmodium falciparum in vitro.

The sensitivities in vitro of Plasmodium falciparum to the benzimidazoles, albendazole, thiabendazole, mebendazole, omeprazole and 2 albendazole metabolites, albendazole sulphone and albendazole sulphoxide, were investigated and compared to those of the commonly used antimalarial drugs chloroquine and quinine. Quinine and chloroquine were the most potent drugs tested (EC50 values of 8 x 10(-9)-6 x 10(-8) mol/L and 5-7 x 10(-9) mol/L, respectively). Thiabendazole, mebendazole, albendazole sulphone and albendazole sulphoxide reached maximum growth inhibitions of 13-36% at the highest concentration tested (1 x 10(-4) mol/L). Albendazole (EC50 range: not achieved-2 x 10(-6) mol/L) and omeprazole (EC50 range: 2-4 x 10(-5) mol/L) were the most effective benzimidazoles. The activity of albendazole was pH dependent, as was that of chloroquine, and variable. Albendazole has its primary mode of action on trophozoites, suggesting that the drug may target parasite tubulin polymerization. Omeprazole, although also primarily effective against trophozoites, had additional activity against schizonts and ring forms, suggesting a distinct or additional parasitic target. Given the variable activity of albendazole and its rapid metabolism in vivo into compounds with even less antimalarial activity, it appears unlikely that this benzimidazole will be useful in the treatment of malaria. The rapid activity and different stage-specific profile of the more soluble benzimidazole omeprazole warrants further investigation.

Animals↗
PubMed1984

Abnormal anti-single stranded (ss) DNA activity in sera from Plasmodium falciparum infected individuals.

Sera from 32 subjects with Plasmodium falciparum parasitaemia were screened for the presence of antibodies to native-double stranded (ds) DNA and to heat-denaturated-single stranded (ss) DNA by a Farr DNA binding radioimmunoassay. In addition anti-dsDNA antibodies were also studied by indirect immunofluorescence using Crithidia luciliae and rat liver sections as substrates. Immunoglobulin (G, A, M) levels and plasmodial antibodies titres (PA) were concomitantly evaluated. The anti-ssDNA activity was higher in malarious individuals with high IgM levels than in normal or malarious individuals with normal IgM levels. This activity was higher during the acute stage of infection than after recovery. A positive and significant relationship was found between the anti-ssDNA activity and the IgM levels but not with IgG, IgA or PA titres. Speckled antinuclear antibodies (ANA) were also observed in sera from 43.8% of the individuals and the mean ssDNA activity was higher in these ANA positive patients. Conversely anti-dsDNA antibodies could not be detected by any of the tests performed. This preferential production of anti-ssDNA Ab and not anti-dsDNA Ab is additional evidence that the autoantibodies observed in malaria infection are not a consequence of a generalized and non-specific polyclonal activation.

Adolescent↗
PubMed2001

An alteration in concatameric structure is associated with efficient segregation of plasmids in transfected Plasmodium falciparum parasites.

Transfection of the human malaria parasite Plasmodium falciparum is currently performed with circularised plasmids that are maintained episomally in parasites under drug selection but which are rapidly lost when selection pressure is removed. In this paper, we show that in instances where gene targeting is not favoured, transfected plasmids can change to stably replicating forms (SRFs) that are maintained episomally in the absence of drug selection. SRF DNA is a large concatamer of the parental plasmid comprising at least nine plasmids arranged in a head-to-tail array. We show as well that the original unstable replicating forms (URFs) are also present as head-to-tail concatamers, but only comprise three plasmids. Limited digestion and gamma irradiation experiments revealed that while URF concatamers are primarily circular, as expected, SRF concatamers form a more complex structure that includes extensive single-stranded DNA. No evidence of sequence rearrangement or additional sequence was detected in SRF DNA, including in transient replication experiments designed to select for more efficiently replicating plasmids. Surprisingly, these experiments revealed that the bacterial plasmid alone can replicate in parasites. Together, these results imply that transfected plasmids are required to form head-to-tail concatamers to be maintained in parasites and implicate both rolling-circle and recombination-dependent mechanisms in their replication.

Animals↗
PubMed2005

Roles of 1-Cys peroxiredoxin in haem detoxification in the human malaria parasite Plasmodium falciparum.

In the present study, we investigated whether Plasmodium falciparum 1-Cys peroxiredoxin (Prx) (Pf1-Cys-Prx), a cytosolic protein expressed at high levels during the haem-digesting stage, can act as an antioxidant to cope with the oxidative burden of haem (ferriprotoporphyrin IX; FP). Recombinant Pf1-Cys-Prx protein (rPf1-Cys-Prx) competed with glutathione (GSH) for FP and inhibited FP degradation by GSH. When rPf1-Cys-Prx was added to GSH-mediated FP degradation, the amount of iron released was reduced to 23% of the reaction without the protein (P < 0.01). The rPf1-Cys-Prx bound to FP-agarose at pH 7.4, which is the pH of the parasite cytosol. The rPf1-Cys-Prx could completely protect glutamine synthetase from inactivation by the dithiothreitol-Fe(3+)-dependent mixed-function oxidation system, and it also protected enolase from inactivation by coincubation with FP/GSH. Incubation of white ghosts of human red blood cells and FP with rPf1-Cys-Prx reduced formation of membrane associations with FP to 75% of the incubation without the protein (P < 0.01). The findings of the present study suggest that Pf1-Cys-Prx protects the parasite against oxidative stresses by binding to FP, slowing the rate of GSH-mediated FP degradation and consequent iron generation, protecting proteins from iron-derived reactive oxygen species, and interfering with formation of membrane-associated FP.

Animals↗
PubMed2005

Novel alleles of Plasmodium falciparum dhfr that confer resistance to chlorcycloguanil.

In Plasmodium falciparum, resistance to folate inhibitors like pyrimethamine is mediated by point mutations in the target gene dihydrofolate reductase (dhfr). The resistance to pyrimethamine increases with the accumulation of particular point mutations. These mutations also confer increased resistance to chlorcycloguanil, the active metabolite of chlorproguanil and one component of a newly introduced DHFR inhibitor, LapDap. One genotype (16V/108T) has been previously identified that confers resistance to cycloguanil but not to pyrimethamine. This study was designed to identify novel alleles that might confer resistance to chlorcycloguanil, but escape the surveillance methods currently in place for common pyrimethamine-resistant alleles. Directed mutagenesis was performed using the wild type and the common pyrimethamine-resistant allele, 51I/59R/108N, to determine the effect of the 16V and 108T mutations on enzyme activity and drug resistance. In addition, we randomly mutagenized the 51I/59R/108N allele and identified nine novel alleles that could confer resistance to chlorcycloguanil. These yeast strains were also resistant to pyrimethamine, but retained sensitivity to the experimental DHFR inhibitor, WR99210. None of the alleles generated in this study was as resistant to chlorcycloguanil as the common quadruple mutant, 51I/59R/108N/164L. In addition, selection of high levels of chlorcycloguanil resistance in parasites that carry the 51I/59R/108N allele will require two directed steps, a change from 108N to 108T followed by a mutation from A16 to 16V. The resulting allele, 16V/51I/59R/108T is highly resistant to chlorcycloguanil, but 200-fold more sensitive to pyrimethamine than the 51I/59R/108N allele.

Alleles↗
PubMed1999

Essential protein-protein interactions between Plasmodium falciparum thymidylate synthase and dihydrofolate reductase domains.

In Plasmodium falciparum, dihydrofolate reductase and thymidylate synthase activities are conferred by a single 70-kDa bifunctional polypeptide (DHFR-TS, dihydrofolate reductase-thymidylate synthase) which assembles into a functional 140-kDa homodimer. In mammals, the two enzymes are smaller distinct molecules encoded on different genes. A 27-kDa amino domain of malarial DHFR-TS is sufficient to provide DHFR activity, but the structural requirements for TS function have not been established. Although the 3'-end of DHFR-TS has high homology to TS sequences from other species, expression of this protein fragment failed to yield active TS enzyme, and it failed to complement TS(-) Escherichia coli. Unexpectedly, even partial 5'-deletion of full-length DHFR-TS gene abolished TS function on the 3'-end. Thus, it was hypothesized that the amino end of the bifunctional parasite protein plays an important role in TS function. When the 27-kDa amino domain (DHFR) was provided in trans, a previously inactive 40-kDa carboxyl-domain from malarial DHFR-TS regained its TS function. Physical characterization of the "split enzymes" revealed that the 27- and the 40-kDa fragments of DHFR-TS had reassembled into a 140-kDa hybrid complex. Thus, in malarial DHFR-TS, there are physical interactions between the DHFR domain and the TS domain, and these interactions are necessary to obtain a catalytically active TS. Interference with these essential protein-protein interactions could lead to new selective strategies to treat malaria resistant to traditional DHFR-TS inhibitors.

Animals↗
PubMedDate not supplied

Comparative protein modeling of 1-deoxy-D-xylulose-5-phosphate reductoisomerase enzyme from Plasmodium falciparum: a potential target for antimalarial drug discovery.

Plasmodium falciparum 1-deoxy-D-xylulose-5-phosphate reductoisomerase (Pf-DXR) is a potential target for antimalarial chemotherapy. The three-dimensional model (3D) of this enzyme was determined by means of comparative modeling through multiple alignment followed by intensive optimization, minimization, and validation. The resulting model demonstrates a reasonable topology as gauged from the Ramachandran plot and acceptable three-dimensional structure compatibility as assessed by the Profiles-3D score. The modeled monomeric subunit consists of three domains: (1) N-terminal NADPH binding domain, (2) connective or linker domain (with most of the active site residues located in this domain), and (3) a C-terminal domain. This structure proved to be consistent with known DXR crystal structures from other species. The predicted active site compared favorably with those of the templates and appears to have an active site with a highly conserved architecture. Additionally, the model explains several site-directed mutagenesis data. Besides using several protein structure-checking programs to validate the model, a set of known inhibitors of DXR were also docked into the active site of the modeled Pf-DXR. The docked scores correlated reasonably well with experimental pIC50 values with a regression coefficient (R2) equal to 0.84. Results of the current study should prove useful in the early design and development of inhibitors by either de novo drug design or virtual screening of large small-molecule databases leading to development of new antimalarial agents.

Aldose-Ketose Isomerases↗
PubMed1996

Effect of pH on in vitro potency of amantadine against Plasmodium falciparum.

Amantadine is a monoprotic weak base that inhibits intraerythrocytic growth in in vitro cultures of Plasmodium falciparum, specifically chloroquine-resistant strains. Changes in the external PH of the medium are expected to result in a shift in the relative proportion of ionized and unionized species of amantadine by virtue of the weak base characteristic of the drug, influencing passage of the drug through the membrane. The ability of amantadine to alkalinize the food vacuole was determined using the accumulation of acridine orange as a vacuolar probe. Drug sensitivity following alteration of the pH gradient was assessed using the hypoxanthine method. Amantadine was able to alkalinize the food vacuole in the millimolar range; however, since its antimalarial activity is in the micromolar range, alkalinization of the food vacuole is not the primary action of the drug. The pH of the medium profoundly influenced susceptibility to chloroquine; the log of the 50% inhibitory concentration (IC50) values were linearly dependent on the external pH in both chloroquine-resistant and chloroquine-sensitive strains. Log IC50 values of amantadine exhibited a linear dependence on external pH in the chloroquine-sensitive strain, but in the chloroquine-resistant strain, a nonlinear parabolic function was found with the minimum IC50 at pH 7.03. Ammonium chloride did not interfere with the antimalarial activity of amantadine. The presence of the amine group on the hydrocarbon cage is essential for the activity of amantadine in Plasmodium falciparum. These results suggest factors in addition to pH gradient are involved in the effect of amantadine, possibly interactions with membrane phospholipids.

Adamantane↗
PubMed2001

A prodrug form of a Plasmodium falciparum glutathione reductase inhibitor conjugated with a 4-anilinoquinoline.

Glutathione (GSH), which is known to guard Plasmodium falciparum from oxidative damage, may have an additional protective role by promoting heme catabolism. An elevation of GSH content in parasites leads to increased resistance to chloroquine (CQ), while GSH depletion in resistant P. falciparum strains is expected to restore the sensitivity to CQ. High intracellular GSH levels depend inter alia on the efficient reduction of GSSG by glutathione reductase (GR). On the basis of this hypothesis, we have developed a new strategy for overcoming glutathione-dependent 4-aminoquinoline resistance. To direct both a 4-aminoquinoline and a GR inhibitor to the parasite, double-drugs were designed and synthesized. Quinoline-based alcohols (with known antimalarial activity) were combined with a GR inhibitor via a metabolically labile ester bond to give double-headed prodrugs. The biochemically most active double-drug 7 of this series was then evaluated as a growth inhibitor against six Plasmodium falciparum strains that differed in their degree of resistance to CQ; the ED(50) values for CQ ranged from 14 to 183 nM. While the inhibitory activity of the original 4-aminoquinoline-based alcohol followed that of CQ in these tests, the double-drug exhibited similar efficiency against all strains, the ED(50) being as low as 28 nM. For the ester 7, a dose-dependent decrease in glutathione content and GR activity and an increase in glutathione-S-transferase activity were determined in treated parasites. The drug was subsequently tested for its antimalarial action in vivo using murine malaria models infected with P. berghei. A 178% excess mean survival time was determined for the animals treated with 40 mg/kg 7 for 4 days. No cytotoxicity due to this compound was observed. Work is in progress to extend and validate the strategy outlined here.

Aniline Compounds↗
PubMed1994

Enhanced expression of Plasmodium falciparum heat shock protein PFHSP70-I at higher temperatures and parasite survival.

The effect of various body temperatures, encountered during malaria fever, on the synthesis of Plasmodium falciparum heat-shock protein called PFHSP70-I and parasite growth rates among five different isolates are described. The results show that after the exposure of parasites at 39 degrees C for 30 min the amount of PFHSP70-I in all five isolates increased markedly and significantly, whereas parasite growth rates and the amount of total blood stage antigens remained almost unaffected. This indicates that the PFHSP70-I gene responds to heat-shock by producing higher amounts of PFHSP70-I protein, presumably to protect the parasite from being killed during malaria fever.

Animals↗
PubMed1996

The gamma/delta T-cell response to Plasmodium falciparum malaria in a population in which malaria is endemic.

Frequencies and absolute numbers of peripheral gamma/delta T cells have been reported to increase after episodes of Plasmodium falciparum malaria in adults with limited or no previous malaria exposure. In contrast, little is known about the gamma/delta T-cell response to malaria in children from areas where malaria is endemic, who bear the burden of malaria-related morbidity and mortality. We investigated the gamma/delta T-cell response in 19 Ghanaian children from an area of hyperendemic, seasonal malaria transmission. The children presented with cerebral malaria (n = 7), severe malarial anemia (n = 5), or uncomplicated malaria (n = 7) and were monitored from admission until 4 weeks later. We found no evidence of increased frequencies of gamma/delta T cells in any of the patient groups, whereas one adult expatriate studied in Ghana and three adults admitted to the hospital in Copenhagen, Denmark, all with uncomplicated, primary P. falciparum malaria, showed increased gamma/delta T-cell frequencies similar to those previously reported. All patients had lowered absolute numbers of peripheral gamma/delta T cells at admission, changing to increased numbers by days 7 to 14 and then returning to normal levels. The study raises questions regarding age and degree of previous exposure as determinants of malaria-induced gamma/delta T-cell responses.

Adult↗
PubMed2004

Resistance of early midgut stages of natural Plasmodium falciparum parasites to high temperatures in experimentally infected Anopheles gambiae (Diptera: Culicidae).

We studied the effects of high temperature, 30 and 32 versus 27 C on early Plasmodium falciparum development in Anopheles gambiae experimentally infected with gametocytes from 30 volunteers with mean density of 264.1 gametocytes/microl blood (range: 16-1,536/microl). From several batches of mosquitoes, fed by membrane feeding, midguts of individual mosquitoes were dissected at 24 hr for ookinete enumeration and at 7 days to quantify oocysts. There were temperature-related differences in mean ookinete intensity per mosquito midgut, with 9.71 +/- 1.6 at 27 C, 9.85 +/- 2.32 at 30 C, and 3.89 +/- 0.81 at 32 C. The prevalence of oocyst infection decreased with an increase in temperatures from 15.9 to 8.5 to 6.4% at 27, 30, and 32 C, respectively. The average oocyst intensities for the infected mosquitoes increased with temperatures from 2.9 at 27 C to 3.5 at 30 C, and to 3.3 at 32 C. However, the success of infections was reduced at 30 and 32 C, and resulted in greater losses during consecutive inter-stage parasite development. The most significant impact of high temperatures occurred at the transition between macrogametocytes and ookinetes, whereas the transition between ookinetes and oocysts apparently was not affected. In contrast to other reports, exposure of mosquitoes infected with natural parasites to high temperatures did not eliminate preoocyst stages, as has been observed from laboratory studies using the NF-54 strain of P. falciparum. This observation of parasite resistance to high temperatures is consistent with the natural situation in tropical environments where perennial malaria transmission occurs during hot dry seasons.

Adolescent↗
PubMed2005

Molecular epidemiology of Plasmodium falciparum resistance to antimalarial drugs in Indonesia.

The extent of gene polymorphisms associated with resistance to chloroquine and sulfadoxine-pyrimethamine was examined in field isolates of Plasmodium falciparum from Indonesia. Eight malaria-endemic areas, representing a broad region of the western and eastern Indonesian Archipelago were surveyed. Blood from 20-50 patients was collected at each site, DNA was isolated, and the sequences of four different genes (dihydrofolate reductase [dhfr], dihydropteroate synthase [dhps], P. falciparum multidrug resistance 1 [pfmdr1], and P. falciparum chloroquine resistance transporter [pfcrt]) were analyzed using polymerase chain reaction and restriction fragment length polymorphisms to detect polymorphisms previously shown to be associated with resistance. This analysis identified polymorphisms in dhfr at 108-Asn/Thr, 16-Val, and 59-Arg. Polymorphisms in dhps were found less frequently, either 437-Gly alone or paired with 540-Glu. The pfcrt 76-Thr polymorphism was fixed in all parasite populations and pfmdr1 86-Tyr polymorphisms in all populations except in the most eastern regions. The pfmdr1 1042-Asp polymorphism occurred less frequently. These findings indicate that polymorphisms in genes associated with drug resistance in P. falciparum are found across a broad region of Indonesia.

ATP-Binding Cassette Transporters↗
PubMed1994

[Detection of Plasmodium falciparum by polymerase chain reaction (PCR)].

A pair of primers were designed and synthesized based on the DNA fragment coded erythrocyte-binding antigen (EBA-175) of Plasmodium falciparum (P.f.) and polymerase chain reaction (PCR) was performed to detect P.f. cultured in vitro. The amplified products were analysed by agarose gel electrophoresis and a specific 492 bp DNA band was showed in P.f. infected blood sample, but no band showed in P. vivax, P. cynomolgi, P. yoelii and P. berghei infected blood samples, nor in normal one. The parasite densities detected by this method could be as minimal as 10 parasites/20 microliters blood. The PCR technique showed high sensitivity and specificity.

Animals↗
PubMedDate not supplied

[Evaluation of Plasmodium falciparum susceptibility to chloroquine and amodiaquine using a simplified, in vivo, 7-day test in southern Cameroon].

Plasmodium falciparum susceptibility to chloroquine and amodiaquine at a posology of 25 mg/kg per os in 3 days was evaluated in the pupils of 6 primary schools of South-West Cameroon during the first semester 1989. Parasitic index was 75%. Plasmodium falciparum was present in 96% of the infections 24% of the 357 children treated with chloroquine were carriers of trophozoites at D3 and 17% at D7. Complete resistance, at level R III, was observed in 4% of the children. By the 55 children treated with amodiaquine, 13% and 10% were carriers of few trophozoites at D3 and D7. The significance of these results is discussed.

Adolescent↗
PubMed2004

Genetic diversity in the merozoite surface protein 1 gene of Plasmodium falciparum in different malaria-endemic localities.

A number of stage-specific antigens have been characterized for vaccine development in Plasmodium falciparum malaria. The polymorphic merozoite surface protein 1 (MSP-1) of Plasmodium falciparum is a major asexual blood stage malaria vaccine candidate antigen. In the present study, we analyzed the impact of hyperendemic malaria transmission, mesoendemic malaria transmission, and multiple infection on allelic diversity. We have used a simple strategy of polymerase chain reaction amplification and slot-blot hybridization to analyze variable regions of block-2, block-4 and blocks 6-10 of the MSP-1 gene. The allelic types of isolates collected from regions of hyperendemic malaria transmission (RHEMT) and mesoendemic malaria transmission (RMEMT) were compared. In RHEMT, 20 of 24 possible gene types were found among 163 isolates and more than one allelic type was found in 82 (50.3%) of the isolates. Thirteen of 24 possible gene types were found among 125 isolates in RMEMT and 27 (21.6%) of them contained more than one allele type. Our results suggest for the first time that the allelic distribution or allelic diversity and chances of finding multi-strain parasites in isolates in an area vary with the rate of transmission. Analyses of isolates containing more than one strain of parasite suggest that allelic types are randomly distributed, no specific type of alleles predominately show multi-strain infection, and neither strain of the parasite affect the process of infection and development of another.

Alleles↗
PubMed1999

Plasmodium falciparum resistance to sulfadoxine/pyrimethamine in Uganda: correlation with polymorphisms in the dihydrofolate reductase and dihydropteroate synthetase genes.

The efficacy of sulfadoxine/pyrimethamine (S/P) in treatment of uncomplicated falciparum malaria in Africa is increasingly compromised by development of resistance. The occurrence of active site mutations in the Plasmodium falciparum gene sequences coding for dihydrofolate reductase (DHFR) and dihydropteroate synthetase (DHPS) is known to confer resistance to pyrimethamine and sulfadoxine. This study investigated the occurrence of these mutations in infected blood samples taken from Ugandan children before treatment with S/P and their relationship to parasite breakthrough by day 7. The results confirm the occurrence of mutations in DHFR and DHPS that were significantly selected under S/P pressure at day 7: a combination of alleles 51-isoleucine and 108-asparagine in DHFR, and 436-serine, 437-alanine, 540-lysine and 581-alanine in DHPS, appears to play a major role in the development of in vivo resistance in P. falciparum strains against S/P. Therefore, earlier results derived from isolates from hyperendemic areas in Tanzania were confirmed by this investigation.

Animals↗
PubMed1999

Factors influencing resistance to reinfection with Plasmodium falciparum.

A treatment-reinfection study design was used to investigate the relationships between host immunologic and/or genetic factors and resistance to reinfection with Plasmodium falciparum. Sixty-one children in Gabon were enrolled in a cross-sectional study to measure the prevalence of each human plasmodial species. All were given amodiaquine for radical cure of parasites, and 40 were subsequently followed-up for 30 weeks. Successive blood smears were examined to measure the delay of reappearance in blood of asexual stages of P. falciparum parasites. Presence of infection during the cross-sectional survey was associated with male sex, non-deficient glucose-6-phosphate dehydrogenase activity, plasma interleukin-10 level, and anti-LSA-Rep antibody concentration. Resistance to reinfection was related to the presence of anti-LSA-J antibodies, and the absence of anti-LSA-Rep antibodies. Moreover, P. malariae-infected subjects were usually co-infected with P. falciparum, and were also more rapidly reinfected with P. falciparum after treatment, compared with those without P. malariae infection.

Adolescent↗