A plastid organelle as a drug target in apicomplexan parasites.
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). Recent studies have identified an unusual organelle in these parasites: a plastid that appears to have been acquired by secondary endosymbiosis of a green alga. 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 antibiotics, which have been proposed to target protein synthesis in the apicoplast. 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.
Fichera
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Department of Biology, University of Pennsylvania, Philadelphia 19104-6018, USA.
Roos
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D000818:Animals; D000900:Anti-Bacterial Agents / Q000494:pharmacology; D000890:Anti-Infective Agents / Q000494:pharmacology*; D017963:Azithromycin / Q000494:pharmacology; D002701:Chloramphenicol / Q000494:pharmacology; D002939:Ciprofloxacin / Q000494:pharmacology*; D002981:Clindamycin / Q000494:pharmacology; D003049:Coccidiostats / Q000494:pharmacology*; D004261:DNA Replication / Q000187:drug effects; D018628:Gene Dosage; D006801:Humans; D018087:Plastids / Q000187:drug effects* / Q000235:genetics; D059005:Topoisomerase II Inhibitors; D014122:Toxoplasma / Q000187:drug effects* / Q000201:enzymology / Q000648:ultrastructure
D000900:Anti-Bacterial Agents; D000890:Anti-Infective Agents; D003049:Coccidiostats; D059005:Topoisomerase II Inhibitors; D002981:Clindamycin; D002939:Ciprofloxacin; D002701:Chloramphenicol; D017963:Azithromycin