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). 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.

GFP‐targeting allows visualization of the apicoplast throughout the life cycle of live malaria parasites

“…It has been known for some time that asexual blood stages of P. falciparum and the closely related parasite Toxoplasma gondii can be killed by antibiotics, with these drugs frequently causing what is known as a delayed-death phenotype (Geary and Jensen, 1983;Fichera and Roos, 1997). It has been shown for some antibiotics that this killing mechanism results from targeting of the apicoplast with drugs inhibiting DNA replication, transcription or translation within this organelle and thus interfering with essential apicoplast functions (Fichera and Roos, 1997;Dahl et al, 2006;Dahl and Rosenthal, 2007;Goodman et al, 2007).…”

“…It has been shown for some antibiotics that this killing mechanism results from targeting of the apicoplast with drugs inhibiting DNA replication, transcription or translation within this organelle and thus interfering with essential apicoplast functions (Fichera and Roos, 1997;Dahl et al, 2006;Dahl and Rosenthal, 2007;Goodman et al, 2007). We initially investigated whether treatment of exo-erythrocytic stage parasites with certain antibiotics leads to a disruption in the normal development of the apicoplast.…”

“…Similar to other apicomplexa, Plasmodium parasites harbour a plastid-like organelle that is known as the apicoplast, which is generally believed to have arisen by the engulfment of a cyanobacterium. This organelle, similar to the mitochondrion, contains its own genome and is required for parasite survival (Fichera and Roos, 1997;McConkey et al, 1997). The apicoplast genome is only 35 kb in size and, as with the apicomplexan mitochondrion, many proteins functioning within the apicoplast are encoded in the nuclear genome and targeted post-translationally to the apicoplast (Wilson et al, 1996;Foth et al, 2003).…”

Role of phosphatidic acid in plant galactolipid synthesis

“…These unicellular eukaryotes harbour a non-photosynthetic plastid, the apicoplast, which is involved in vital metabolic pathways, one of them being lipid biosynthesis [4,38,39]. The demand in lipids required for parasite maintenance is met by combination of scavenging fatty acids from their host and de novo synthetic pathway [40].…”

Quinoline Derivative MC1626, a Putative GCN5 Histone Acetyltransferase (HAT) Inhibitor, Exhibits HAT-Independent Activity against Toxoplasma gondii

“…2). Parasites treated with fluoroquinolones such as ciprofloxacin no longer exhibit this staining pattern because of the loss of apicoplast DNA (9). To test if MC1626 functions similarly, we examined if Toxoplasma maintained in 200 M MC1626 exhibited a decrease in the number of parasites containing apicoplasts.…”