The plastid-derived organelle of protozoan human parasites as a target of established and emerging drugs.
Human diseases like malaria, toxoplasmosis or cryptosporidiosis are caused by intracellular protozoan parasites of the phylum Apicomplexa and are still a major health problem worldwide. In the case of Plasmodium falciparum, the causative agent of tropical malaria, resistance against previously highly effective drugs is widespread and requires the continued development of new and affordable drugs. Most apicomplexan parasites possess a single plastid-derived organelle called apicoplast, which offers the great opportunity to tailor highly specific inhibitors against vital metabolic pathways resident in this compartment. This is due to the fact that several of these pathways, being of bacterial or algal origin, are absent in the mammalian host. In fact, the targets of several antibiotics already in use for years against some of these diseases can now be traced to the apicoplast and by knowing the molecular entities which are affected by these substances, improved drugs or drug combinations can be envisaged to emerge from this knowledge. Likewise, apicoplast-resident pathways like fatty acid or isoprenoid biosynthesis have already been proven to be the likely targets of the next drug generation. In this review the current knowledge on the different targets and available inhibitors (both established and experimental) will be summarised and an overview of the clinical efficacy of drugs that inhibit functions in the apicoplast and which have been tested in humans so far will be given.
Wiesner
Jochen
J
Justus-Liebig-Universität Giessen, Biochemisches Institut, Friedrichstr. 24, D-35392 Giessen, Germany.
Seeber
Frank
F
D000818:Animals; D000900:Anti-Bacterial Agents / Q000008:administration & dosage / Q000737:chemistry; D000981:Antiprotozoal Agents / Q000008:administration & dosage* / Q000737:chemistry; D016503:Drug Delivery Systems / Q000379:methods*; D015507:Drugs, Investigational / Q000008:administration & dosage*; D006801:Humans; D008288:Malaria / Q000188:drug therapy / Q000469:parasitology; D015388:Organelles / Q000187:drug effects / Q000469:parasitology; D018087:Plastids / Q000187:drug effects* / Q000469:parasitology*
D000900:Anti-Bacterial Agents; D000981:Antiprotozoal Agents; D015507:Drugs, Investigational