Targeting the transcriptional and translational machinery of the endosymbiotic organelle in apicomplexans.
Apicomplexans are obligate intracellular parasites causing devastating disease in both humans and livestock. Nearly all apicomplexans, with the exception of Cryptosporidium, contain two endosymbiontic organelles carrying their own DNA; the mitochondrion and the plastid-like organelle called the apicoplast. The apicoplast is an attractive drug target as it harbors not only metabolic pathways not found in the host cell, but it is also dependent on its ancient transcriptional and translational machinery. These parasites rely on the plastid, and inhibition of its function or loss of this organelle leads to immediate or delayed death. Replication of plastidic DNA shows differences between the members of this phylum. In Plasmodium parasites, two forms of replication are observed--unidirectional single-stranded replication and a rolling circle mechanism--whereas in Toxoplasma gondii only the rolling circle is found. Targeting enzymes involved in DNA-replication leads to a delayed death of the parasite. Most of the genes in the apicoplast genome encode elements of their own transcriptional and translational machinery, and they are highly similar to those found in bacteria. Several anti-bacterials which target this machinery are also active against apicomplexan parasites and inhibition leads mostly to the delayed death phenomenon.
Fleige
Tobias
T
Department of Microbiology and Molecular Medicine, CMU, University of Geneva, 1 rue Michel-Servet, 1211 Geneva 4, Switzerland. Tobias.Fleige@medecine.unige.ch
Soldati-Favre
Dominique
D
D000818:Animals; D000981:Antiprotozoal Agents / Q000494:pharmacology*; D016782:Apicomplexa / Q000187:drug effects* / Q000235:genetics / Q000378:metabolism; D004261:DNA Replication / Q000187:drug effects; D054627:Genome, Plastid / Q000235:genetics; D008954:Models, Biological; D015388:Organelles / Q000187:drug effects* / Q000235:genetics / Q000378:metabolism; D018087:Plastids / Q000187:drug effects / Q000235:genetics / Q000378:metabolism; D014176:Protein Biosynthesis / Q000187:drug effects; D014158:Transcription, Genetic / Q000187:drug effects
D000981:Antiprotozoal Agents