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A plastid organelle as a drug target in apicomplexan parasites

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.

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Figure 1: DAPI staining of intracellular parasites treated with ciprofloxacin reveals a loss of apicoplast DNA.
Figure 2: Quantitative Southern blots showing that ciprofloxacin and clindamycin selectively reduce plastid genome copy number relative to genomic nuclear DNA.
Figure 3: Ciprofloxacin and clindamycin inhibit intracellular tachyzoite division with the same peculiar kinetics.

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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.

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Correspondence to David S. Roos.

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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

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