Therapeutic potential of folate uptake inhibition in Plasmodium falciparum

doi:10.1016/j.pt.2003.12.005

Trends in Parasitology

Volume 20, Issue 3, March 2004, Pages 109-112

https://doi.org/10.1016/j.pt.2003.12.005 Get rights and content

Abstract

Plasmodium falciparum parasites resistant to the combination sulfadoxine–pyrimethamine are spreading in Africa, particularly in East Africa. This is a matter of concern because there are no other affordable drugs available. This article provides the evidence indicating that sulfadoxine–pyrimethamine resistance can be reversed in vitro and discusses how this information might be exploited to extend the therapeutic lifetime of sulfadoxine–pyrimethamine in vivo.

Section snippets

Inhibition of folate uptake

In P. falciparum, studies have demonstrated that the addition of folate derivatives (folic acid or folinic acid) decreases the activity of antifolate drugs, both in vitro and in vitro 6, 7, 8. Likewise, the lowering of folate concentration in in vitro culture medium enhances the activity of antifolate antimalarial agents 9, 10. This clearly shows that folate uptake contributes significantly to antifolate drug efficacy. Therefore, it is surprising that inhibition of the folate uptake pathway has

Effect of probenecid on antifolate activity in vitro

The effect and the impact of PBN on the activity of antimalarial antifolates in vitro and on the uptake of folic acid into the parasitized erythrocyte, respectively, have been assessed.

Possible mode of action of probenecid

There have been several studies investigating the mode of action of PBN in mammalian cells (cancer cells). PBN has two effects on cancer cells: (i) PBN reverses methotrexate resistance [20]; and (ii) PBN increases the activity of other antifolates [11]. Molecular analyses have shown that the ability of PBN to reverse methotrexate resistance is associated with the inhibition of MRPs. MRPs are overexpressed in methotrexate-resistant cells, which is correlated to an increase of methotrexate

A potential therapeutic strategy?

PBN has been available for >50 years and is still used for a range of clinical conditions (e.g. the management of gout) and in combination with penicillin to increase the duration of penicillin action. Pharmacokinetics properties and the toxicity profile of PBN have been studied extensively [31]. The highest recommended dose of PBN for adults is 3 g. A dose of 2 g (normal dose) yields circulating plasma concentrations ranging between 500 and 700 μM. At these therapeutic doses, PBN has an

Conclusion

For the first time, it has been reported that PBN, an inhibitor of anion transporter, has the ability to increase antifolate activity in P. falciparum. However, many questions remain. The relevant transporter(s) needs to be identified and fully characterized as a vital step towards rational potentiator design. The effect of PBN in humans when used with synergistic antifolate combinations should also be assessed, although it is predicted that these effects would be greater than that seen with

Acknowledgements

We thank the director of Kenya Medical Research Institute for permission to publish these data. This work was supported by the Wellcome Trust (no. 056769). A.N. and K.M. are grateful to the Wellcome Trust for personal support. P.W. and S.A.W. are grateful to the Wellcome Trust for institutional support.

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Trends in Parasitology

Research FocusTherapeutic potential of folate uptake inhibition in Plasmodium falciparum

Abstract

Section snippets

Inhibition of folate uptake

Effect of probenecid on antifolate activity in vitro

Possible mode of action of probenecid

A potential therapeutic strategy?

Conclusion

Acknowledgements

Lancet

Lancet

Trends Parasitol.

Trans. R. Soc. Trop. Med. Hyg.

Mol. Biochem. Parasitol.

Prog. Nucleic Acid Res. Mol. Biol.

Biochim. Biophys. Acta

Biochim. Biophys. Acta

Biochim. Biophys. Acta

Parasitol. Today

Towards an understanding of the mechanism of pyrimethamine-sulfadoxine resistance in Plasmodium falciparum: genotyping of dihydrofolate reductase and dihydropteroate synthase of Kenyan parasites

Antimicrob. Agents Chemother.

Treatment history and treatment dose are important determinants of sulfadoxine-pyrimethamine efficacy in children with uncomplicated malaria in Western Kenya

J. Infect. Dis.

The antimalarial triazine WR99210 and the prodrug PS-15: folate reversal of in vitro activity against Plasmodium falciparum and a non-antifolate mode of action of the prodrug

Am. J. Trop. Med. Hyg.

A modified in vitro sulfadoxine susceptibility assay for Plasmodium falciparum suitable for investigating Fansidar resistance

Parasitology

Utilization of exogenous folate in the human malaria parasite Plasmodium falciparum and its critical role in antifolate drug synergy

Mol. Microbiol.

Research Focus
Therapeutic potential of folate uptake inhibition in Plasmodium falciparum