Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

Triclosan offers protection against blood stages of malaria by inhibiting enoyl-ACP reductase of Plasmodium falciparum

A Correction to this article was published on 01 May 2001

Abstract

The antimicrobial biocide triclosan [5-chloro-2-(2,4-dichlorophenoxy)phenol] potently inhibits the growth of Plasmodium falciparum in vitro and, in a mouse model, Plasmodium berghei in vivo. Inhibition of [14C]acetate and [14C]malonyl-CoA incorporation into fatty acids in vivo and in vitro, respectively, by triclosan implicate FabI as its target. Here we demonstrate that the enoyl-ACP reductase purified from P. falciparum is triclosan sensitive. Also, we present the evidence for the existence of FabI gene in P. falciparum. We establish the existence of the de novo fatty acid biosynthetic pathway in this parasite, and identify a key enzyme of this pathway for the development of new antimalarials.

This is a preview of subscription content, access via your institution

Relevant articles

Open Access articles citing this article.

Access options

Buy article

Get time limited or full article access on ReadCube.

$32.00

All prices are NET prices.

Figure 1: In vitro antimalarial activity of triclosan.
Figure 2: Inhibition of fatty acid synthesis by triclosan.
Figure 3: Enoyl-ACP reductase of P. falciparum.
Figure 4: FabI gene of the parasite.

References

  1. Rock, C.O. & Cronan, J.E. Escherichia coli as a model for the regulation of dissociable (type II) fatty acid biosynthesis. Biochim. Biophys. Acta. 1302, 1–16 (1996).

    Article  Google Scholar 

  2. Weeks, G. & Wakil, S.J. Studies on the mechanism of fatty acid synthesis. J. Biol. Chem. 243, 1180–1189 (1968).

    CAS  PubMed  Google Scholar 

  3. Turnowsky, F., Fuchs, K., Jeschek, C. & Högenauer, G. envM genes of Salmonella typhimurium and Escherichia coli. J. Bacteriol. 171, 6555–6565 (1989).

    Article  CAS  Google Scholar 

  4. Bergler, H. et al. Protein EnvM is the NADH-dependent enoyl-ACP reductase (FabI) of Escherichia coli. J. Biol. Chem. 269, 5493–5496 (1994).

    CAS  PubMed  Google Scholar 

  5. Heath, R.J. & Rock, C.O. Enoyl-acyl carrier protein reductase (FabI) plays a determinant role in completing cycles of fatty acid elongation in Escherichia coli. J. Biol. Chem. 44, 26538–26542 (1995).

    Article  Google Scholar 

  6. Waller, R.F. et al. Nuclear-encoded proteins target to the plastid in Toxoplasma gondii and Plasmodium falciparum. Proc. Natl. Acad. Sci. USA 95, 12352–12357 (1998).

    Article  CAS  Google Scholar 

  7. McMurray, L.M., Oethinger, M. & Levy, S.B. Triclosan targets lipid synthesis. Nature 394, 531–532 (1998).

    Article  Google Scholar 

  8. Heath, R.J., Yu, Y.-T., Shapiro, M.A., Olson, E. & Rock, C.O. Broad spectrum antimicrobial biocides target the FabI component of fatty acid synthesis. J. Biol. Chem. 273, 30316–30320 (1998).

    Article  CAS  Google Scholar 

  9. Heath, R.J. et al. Mechanism of triclosan inhibition of bacterial fatty acid synthesis. J. Biol. Chem. 274, 11110–11114 (1999).

    Article  CAS  Google Scholar 

  10. Vance, D., Goldberg, I., Mitsuhashi, O. & Bloch, K. Inhibition of fatty acid synthetases by the antibiotic cerulenin. Biochem. Biophys. Res. Commun. 48, 649–656 (1972).

    Article  CAS  Google Scholar 

  11. Mitruka, M. & Rawnsley, H.M. Clinical, biochemical and hematological reference values in normal experimental animals. (Mason Publishing, New York, 1977).

    Google Scholar 

  12. Matesanz, F., Duran-Chica, I. & Alcina, A. The cloning and expression of pfacs1, a Plasmodium falciparum fatty acid coenzyme A synthetase-1 targeted to the host erythrocyte cytoplasm. J. Mol. Biol. 291, 59–70 (1999).

    Article  CAS  Google Scholar 

  13. Haldar, K., Ferguson, M.A.J. & Cross, G.A.M. Acylation of a Plasmodium falciparum merozoite surface antigen via sn-1,2-diacyl glycerol. J. Biol. Chem. 260, 4969–4974 (1985).

    CAS  PubMed  Google Scholar 

  14. Holz, G.G. Jr. Lipids and the malarial parasite. Bull. World Health Organ. 55, 237–248 (1977).

    CAS  PubMed  PubMed Central  Google Scholar 

  15. Bergler, H., Fuchsbichler, S., Högenauer, G. & Turnowsky, F. The enoyl-[acyl-carrier-protein] reductase (FabI) of Escherichia coli, which catalyzes a key regulatory step in fatty acid biosynthesis, accepts NADH and NADPH as cofactors and is inhibited by palmitoyl-CoA. Eur. J. Biochem. 242, 689–694 (1996).

    Article  CAS  Google Scholar 

  16. Kater, M.M., Koningstein, G.M., Nijkamp, J.J. & Stuitje, A.R. cDNA cloning and expression of Brassica napus enoyl-acyl carrier protein reductase in Escherichia coli. Plant Mol. Biol. 17, 895–909 (1991).

    Article  CAS  Google Scholar 

  17. Levy, C.W. et al. Molecular basis of triclosan activity. Nature 398, 383–384 (1999).

    Article  CAS  Google Scholar 

  18. McConkey, G.A., Rogers, J.M. & McCutchan, T.F. Inhibition of Plasmodium falciparum protein synthesis. Targeting the plastid-like organelle with thiostrepton. J. Biol. Chem. 272, 2046–2049 (1977).

    Article  Google Scholar 

  19. Razin, S., Yogev, D. & Naot, Y. Molecular biology and pathogenicity of mycoplasmas. Microbiol. Mol. Biol. Rev. 62, 1094–1156 (1998).

    CAS  PubMed  PubMed Central  Google Scholar 

  20. Fraser, C.M. et al. The minimal gene complement of Mycoplasma genitalium. Science 270, 397–403 (1995).

    Article  CAS  Google Scholar 

  21. Himmelreich, H., Hilbert, H., Plagens, H., Herrmann, R. Complete sequence analysis of the genome of the bacterium Mycoplasma pneumoniae. Nucleic Acids Res. 24, 4420–4449 (1996).

    Article  CAS  Google Scholar 

  22. Agarwal, A.K., Singhal, A. & Gupta, C.M. Functional drug targeting to erythrocytes in vivo using antibody bearing liposomes as drug vehicles. Biochem. Biophys. Res. Commun. 148, 357–361 (1987).

    Article  Google Scholar 

  23. Fitch, C.D. et al. Lysis of Plasmodium falciparum by ferriprotoporphyrin IX and a chloroquine-ferriprotoporphyrin IX complex. Antimicrob. Agents Chemother. 21, 819–822 (1982).

    Article  CAS  Google Scholar 

  24. Surolia, N. & Padmanaban, G. Chloroquine inhibits heme-dependent protein synthesis in Plasmodium falciparum. Proc. Natl. Acad. Sci. USA 88, 4786–4790 (1991).

    Article  CAS  Google Scholar 

  25. Jomaa, H. et al. Inhibitors of nonmevalonate pathway of isoprenoid biosynthesis as antimalarial drugs. Science 285, 1573–1576 (1999).

    Article  CAS  Google Scholar 

  26. Bhargava, H.N. & Leonard, P.A. Triclosan application and safety. Am. J. Infect. Control 24, 209–218 (1996).

    Article  CAS  Google Scholar 

  27. Trager, W. & Jenson, J.B. Human malaria parasites in continuous culture. Science 193, 673–675 (1976).

    Article  CAS  Google Scholar 

  28. Rowe, J.A. et al. Implications of mycoplasma contamination in Plasmodium falciparum cultures and methods for its detection and eradication. Mol. Biochem. Parasitol. 92, 177–180 (1998).

    Article  CAS  Google Scholar 

  29. Dussurget, O. & Roulland-Dussoix, D. Rapid, sensitive PCR-based detection of mycoplasmas in simulated samples of animal sera. Appl. Environ. Microbiol. 60, 953–959 (1994).

    CAS  PubMed  PubMed Central  Google Scholar 

  30. Lambros, C. & Vanderberg, J. Synchronization of Plasmodium falciparum erythrocytic stages in culture. J. Parasitol. 65, 418–420 (1979).

    Article  CAS  Google Scholar 

  31. Surolia, N. & Padmanaban, G. De novo biosynthesis of heme offers a new chemotherapeutic target in the human malarial parasite. Biochem. Biophys. Res. Commun. 187, 744–750 (1992).

    Article  CAS  Google Scholar 

  32. Ancelin, M.L. et al. Antimalarial activity of 77 phospholipid polar head analogs: Close correlation between inhibition of phospholipid metabolism and in vitro Plasmodium falciparum growth. Blood 91, 1426–1437 1998).

    CAS  PubMed  Google Scholar 

  33. Peters, W. in Malaria. (ed. Kreier, J.P.) (Academic Press, New York, 1980).

    Google Scholar 

  34. Heusser, D. Dunnschich chromatographic von Fettsauren auf silanisiertem Kiesel gel. J. Chromatogr. 33, 62–69 (1968).

    Article  CAS  Google Scholar 

  35. Slabas, A.R., Sidebottom, C.M., Hellyer, A., Kessell, R.M.J. & Tombs, M.P. Induction, purification and characterization of NADH-specific enoyl acyl carrier protein reductase from developing seeds of oil seed rape (Brassica napus). Biochim. Biophys. Acta 877, 271–280 (1986).

    Article  CAS  Google Scholar 

  36. McKeon, T. & Stumpf, P.K. Purification and characterization of the stearoyl-acyl carrier protein desaturase and the acyl-acyl carrier protein thioesterase from maturing seeds of safflower. J. Biol. Chem. 257, 12141–12147 (1982).

    CAS  PubMed  Google Scholar 

  37. Bradford, M.M. A rapid and sensitive method for the quantitation of microgram quantities of protein utilizing the principle of protein-dye binding. Anal. Biochem. 72, 248–254 (1976).

    Article  CAS  Google Scholar 

  38. Laemmli, U.K. Cleavage of structural proteins during the assembly of the head of bacteriophage T4. Nature 227, 680–685 (1970).

    Article  CAS  Google Scholar 

  39. Chomczynski, P. & Sacchi, N. Single step method of RNA isolation by acid guanidinium thiocyanate-phenol-chloroform extraction. Anal. Biochem. 162, 156–159 (1987).

    Article  CAS  Google Scholar 

  40. Sambrook, J., Fritch, E.F. & Maniatis, T. Molecular Cloning: A Laboratory Manual 2nd ed. (Cold Spring Harbor Laboratory Press, Cold Spring Harbor, New York, 1989).

    Google Scholar 

Download references

Acknowledgements

We thank D. Kamalapriya, T.R. Nagaraja, M. Kapoor, K. Bachhawat, A. Gupta, Kalyani and C. Thomas for technical support; N. Valsala for typographical assistance; R. Uday Kumar for helpful discussions; C.N.R. Rao and G. Padmanaban for encouragement; R. Mula for the gift of triclosan; and the Jawaharlal Nehru Centre for Advanced Scientific Research for financial help. Sequencing of P. falciparum chromosome BLOB was accomplished as part of the Malaria Genome Project with support by The Wellcome Trust.

Author information

Authors and Affiliations

Authors

Corresponding author

Correspondence to Avadhesha Surolia.

Rights and permissions

Reprints and Permissions

About this article

Cite this article

Surolia, N., Surolia, A. Triclosan offers protection against blood stages of malaria by inhibiting enoyl-ACP reductase of Plasmodium falciparum. Nat Med 7, 167–173 (2001). https://doi.org/10.1038/84612

Download citation

  • Received:

  • Accepted:

  • Issue Date:

  • DOI: https://doi.org/10.1038/84612

This article is cited by

Search

Quick links

Nature Briefing

Sign up for the Nature Briefing newsletter — what matters in science, free to your inbox daily.

Get the most important science stories of the day, free in your inbox. Sign up for Nature Briefing