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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.
Korruptionsvorsorge Tag des Gesundheitsamtes Zahl

Apicomplexa are unicellular, obligate intracellular parasites of great medical importance. They include human pathogens like Plasmodium spp., the causative agent of malaria, and Toxoplasma gondii, an opportunistic parasite of immunosuppressed individuals and a common cause of congenital disease (toxoplasmosis). They alone affect several hundred million people worldwide so that new drugs, especially for plasmodial infections, are urgently needed. This review will focus on a recently emerged, potential drug target, a plant-type redox system consisting of ferredoxin- NADP+ reductase (FNR) and its redox partner, ferredoxin (Fd). Both reside in an unique organelle of these parasites, named apicoplast, which is of algal origin. The apicoplast has been shown to be required for pathogen survival. In addition to other pathways already identified in this compartment, the FNR/Fd redox system represents a promising drug target because homologous proteins are not present in host organisms. Furthermore, a wealth of structural information exists on the closely related plant proteins, which can be exploited for structure-function studies of the apicomplexan protein pair. T. gondii and P. falciparum FNRs have been cloned, and the T. gondii enzyme was shown to be a flavoprotein active as a NADPH-dependent oxidoreductase. Both phylogenetic and biochemical analyses indicate that T. gondii FNR is similar in function to the isoform present in non-photosynthetic plastids whereby electron flow is from NADPH to oxidized Fd. The resulting reduced Fd is then presumably used as a reductant for various target enzymes whose nature is just starting to emerge. Among the likely candidates is the iron-sulfur cluster biosynthesis pathway, which is also located in the apicoplast and dependent on reducing power. Furthermore, lipoic acid synthase and enzymes of the isoprenoid biosynthetic pathway may be other conceivable targets. Since all these metabolic steps are vital for the parasite, blocking electron flow from FNR to Fd by inhibition of either FNR activity or its molecular interaction with Fd should also interfere with these pathways, ultimately killing the parasite. Although the three-dimensional structure of FNR from T. gondii is not yet known, experimental and computational evidence shows that apicomplexan and plant enzymes are very similar in structure. Furthermore, single amino acid changes can have profound effects on the enzyme activity and affinity for Fd. This knowledge may be exploited for the design of inhibitors of protein-protein interaction. On the other hand, specifically tailored NAD(P) analogues or mimetics based on previously described substances might be useful lead compounds for apicomplexan FNR inhibitors.
Korruptionsvorsorge Tag des Gesundheitsamtes Zahl

Abbestellung des RKI-Newsletter zu aktuellen Infektionsschutzthemen.
Korruptionsvorsorge Tag des Gesundheitsamtes Zahl

Bestellung des RKI-Newsletters zu aktuellen Infektionsschutzthemen.
Korruptionsvorsorge Tag des Gesundheitsamtes Zahl

Bevor die Mit­ar­beit­erin­nen und Mit­ar­bei­ter das S4-Labor ver­lassen, muss ihr Voll­schutz­an­zug sechs Mi­nu­ten lang in einer spe­ziel­len Dusche de­kon­ta­mi­niert wer­den. Even­tu­ell an­haft­ende Vi­ren wer­den da­durch ge­tötet. Wie alle Ab­wässer aus dem S4-Labor wird auch das Dusch­wasser durch Er­hitzen keim­frei ge­macht.
Korruptionsvorsorge Tag des Gesundheitsamtes Zahl

Alle Materia­lien, die aus dem S4-Labor heraus­trans­portiert wer­den – Labor­ab­fälle, aus­rangierte Ge­räte oder auch Möbel – wer­den in spe­ziellen Ge­räten, so genannten Auto­klaven, be­han­delt: Mit Hilfe von hei­ßem Was­serd­ampf und ent­sprech­en­dem Druck wer­den even­tuell an­haft­ende Er­reger sicher ab­ge­tötet.
Korruptionsvorsorge Tag des Gesundheitsamtes Zahl

Korruptionsvorsorge Tag des Gesundheitsamtes Zahl

Korruptionsvorsorge Tag des Gesundheitsamtes Zahl

Korruptionsvorsorge Tag des Gesundheitsamtes Zahl