Abstract
Parasites of the phylum Apicomplexa include many important human and veterinary pathogens such as Plasmodium (malaria), Toxoplasma (a leading opportunistic infection associated with AIDS and congenital neurological birth defects), and Eimeria (an economically significant disease of poultry and cattle)1,2,3,4. Recent studies have identified an unusual organelle in these parasites5,6,7: a plastid that appears to have been acquired by secondary endosymbiosis of a green alga7. Here we show that replication of the apicomplexan plastid (apicoplast) genome in Toxoplasma gondii tachyzoites can be specifically inhibited using ciprofloxacin, and that this inhibition blocks parasite replication. Moreover, parasite death occurs with peculiar kinetics that are identical to those observed after exposure to clindamycin and macrolide antibiotics8,9, which have been proposed to target protein synthesis in the apicoplast9,10. Conversely, clindamycin (and functionally related compounds) immediately inhibits plastid replication upon drug application—the earliest effect so far described for these antibiotics. Our results directly link apicoplast function with parasite survival, validating this intriguing organelle as an effective target for parasiticidal drug design.
This is a preview of subscription content, access via your institution
Access options
Subscribe to this journal
Receive 51 print issues and online access
$199.00 per year
only $3.90 per issue
Buy this article
- Purchase on Springer Link
- Instant access to full article PDF
Prices may be subject to local taxes which are calculated during checkout
Similar content being viewed by others
References
Levine, N. D. Progress in taxonomy of the Apicomplexan protozoa. J. Protozool. 35, 518–520 (1988).
Luft, B. J. et al . Toxoplasmic encephalitis in patients with the acquired immunodeficiency syndrome. N. Engl. J. Med. 329, 995–1000 (1993).
Roizen, N. et al . Neurologic and developmental outcome in treated congenital toxoplasmosis. Pediatrics 95, 11–20 (1995).
Le Bras, J., Basco, L. K. & de Pecoulas, P. E. Mechanisms and epidemiology of resistance to antimalarials. C. R. Seances Soc. Biol. Fil. 190, 471–485 (1996).
Wilson, R. J. M. et al . Complete gene map of the plastid-like DNA of the malaria parasite Plasmodium falciparum . J. Mol. Biol. 261, 155–172 (1996).
McFadden, G. I., Reith, M. E., Mulholland, J. & Lang-Unnasch, N. Plastid in human parasites. Nature 381, 482 (1996).
Köhler, S. et al . Aplastid of probable green algal origin in apicomplexan parasites. Science 275, 1485–1489 (1997).
Pfefferkorn, E. R., Nothnagel, R. F. & Borotz, S. E. Parasiticidal effect of clindamycin on Toxoplasma gondii grown in cultured cells and selection of a drug-resistant mutant. Antimicr. Agents Chemother. 36, 1091–1096 (1992).
Fichera, M. E., Bhopale, M. K. & Roos, D. S. In vitro assays elucidate peculiar kinetics of clindamycin action against Toxoplasma gondii . Antimicr. Agents Chemother. 39, 1530–1537 (1995).
Beckers, C. J. M. et al . Inhibition of cytoplasmic and organellar protein synthesis in Toxoplasma gondii : Implications for the target of macrolide antibiotics. J. Clin. Invest. 95, 367–376 (1995).
Centers for Disease Control Health Information: http://www.cdc.gov/travel/yellowbk/page128.htm
Haberkorn, A. Chemotherapy of human and animal coccidioses: state and perspectives. Parasitol. Res. 82, 193–199 (1996).
Lane, H. C. Recent advances in the management of AIDS-related opportunistic infections. Ann. Int. Med. 120, 945–955 (1994).
Vogel, G. Parasites shed light on cellular evolution. Science 275, 1422 (1997).
Yoon, C. K. Chloroplasts found in single-celled parasites could be targets for new drug treatments. New York Times, 11 March pC3 (1997).
Furet, Y. X. & Pechere, J. C. Newly documented antimicrobial activity of quinolones. Eur. J. Clin. Microbiol. Infect. Dis. 10, 249–254 (1991).
Lewis, R. J., Tsai, F. T. F. & Wigley, D. B. Molecular mechanisms of drug inhibition of DNA gyrase. BioEssays 18, 661–671 (1996).
Krajcovic, J., Ebringer, L. & Polonyi, J. Quinolones and coumarins eliminate chloroplasts from Euglena gracilis . Antimicr. Agents Chemother. 33, 1883–1889 (1989).
McCabe, R. E. & Oster, S. Current recommendations and future prospects in the treatment of toxoplasmosis. Drugs 38, 973–987 (1989).
Pfefferkorn, E. R., Borotz, S. E. & Nothnagel, R. F. Mutants of Toxoplasma gondii resistant to atovaquone (566C80) or decoquinate. J. Parasitol. 79, 559–564 (1993).
Srivastava, I. K., Rottenberg, H. & Vaidya, A. B. Atovaquone, a broad-spectrum antiparasitic drug, collapses mitochondrial membrane potential in malarial parasites. J. Biol. Chem. 272, 3961–3966 (1997).
Khan, A. A., Slifer, T., Araujo, F. G. & Remington, J. S. Trovafloxacin is active against Toxoplasma gondii . Agents Chemother. 40, 1855–1859 (1996).
Cundliffe, E. in The Ribosome: Structure, Function, and Evolution(eds Hill, W. H. et al.) 479–490 (Am. Soc. Microbiol., Washington DC, (1990).
Araujo, F. G., Shepard, R. M. & Remington, J. S. In vivo activity of the macrolide antibiotics azithromycin, roxithromycin and spiramycin against Toxoplasma gondii . Eur. J. Clin. Microbiol. Infect. Dis. 10, 519–524 (1991).
Dannemann, B. R. et al . Treatment of toxoplasmic encephalitis in patients with AIDS (a randomized trial comparing pyrimethamine plus clindamycin to pyrimethamine plus sulfadiazine). Ann. Intern. Med. 116, 33–43 (1992).
McConkey, G. A., Rogers, M. J. & McCutchan, T. F. Inhibition of Plasmodium falciparum protein synthesis—Targeting the plastid-like organelle with thiostrepton. J. Biol. Chem. 272, 2046–2049 (1997).
Rogers, M. J., Bukhman, Y. V., McCutchan, T. F. & Draper, D. E. Interaction of thiostrepton with an RNA fragment derived from the plastid-encoded ribosomal RNA of the malaria parasite. RNA 3, 1–16 (1997).
Kim, K., Soldati, D. & Boothroyd, J. C. Gene replacement in Toxoplasma gondii with chloramphenicol acetyltransferase as selectable marker. Science 262, 911–914 (1993).
Pfefferkorn, E. R. & Borotz, S. E. Comparison of mutants of Toxoplasma gondii selected for resistance to azithromycin, spiramycin, or clindamycin. Antimicr. Agents Chemother. 38, 31–37 (1994).
Roos, D. S., Donald, R. G. K., Morrissette, N. S. & Moulton, A. L. C. Molecular tools for genetic dissection of the protozoan parasite Toxoplasma gondii . Methods Cell Biol. 45, 28–61 (1994).
Acknowledgements
Ciprofloxacin-HCl was provided by Bayer Corporation, Germany. We thank R. G.K. Donald for probes derived from the apicoplast and nuclear genomes and for developing the quantitative assays for plastid copy number, and members of our laboratory for discussion. This work was supported by research grants and a predoctoral training grant from the NIH. D.S.R. is a New Investigator of the Burroughs Wellcome Fund.
Author information
Authors and Affiliations
Corresponding author
Rights and permissions
About this article
Cite this article
Fichera, M., Roos, D. A plastid organelle as a drug target in apicomplexan parasites. Nature 390, 407–409 (1997). https://doi.org/10.1038/37132
Received:
Accepted:
Issue Date:
DOI: https://doi.org/10.1038/37132
This article is cited by
-
A plastid two-pore channel essential for inter-organelle communication and growth of Toxoplasma gondii
Nature Communications (2021)
-
The anticoccidial activity of the fluoroquinolone lomefloxacin against experimental Eimeria tenella infection in broiler chickens
Parasitology Research (2020)
-
Contribution of introns to the species diversity associated with the apicomplexan parasite, Neospora caninum
Parasitology Research (2020)
-
Inhibitory effects of novel ciprofloxacin derivatives on the growth of four Babesia species and Theileria equi
Parasitology Research (2020)
-
Brazilian strains of Toxoplasma gondii are controlled by azithromycin and modulate cytokine production in human placental explants
Journal of Biomedical Science (2019)
Comments
By submitting a comment you agree to abide by our Terms and Community Guidelines. If you find something abusive or that does not comply with our terms or guidelines please flag it as inappropriate.