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Extra info for Antiparasitic and antibacterial drug discovery: from molecular targets to drug candidates

Sample text

Nifurtimox, on the other hand, caused an increase in nucleotides and nucleobases: it was speculated that this was a consequence of DNA and RNA degradation [112]. The drug combination did not result in any additional changes [112]. Both benznidazole and nifurtimox are used to treat T. cruzi and are thought to have similar modes of action: activation by type 1 NTR and subsequent oxidative stress [107, 178]. Metabolomic analysis of T. cruzi resulted in identification of about 1000 metabolites [107].

Contain a secondary plastid-derived organelle called the apicoplast. This contains various pathways 7 8 1 Discovery the Mechanism of Action and has a genome that encodes the essential proteins [31]; in the blood form, the only apicoplast-specific metabolic pathway that is required for multiplication and survival is isoprenoid biosynthesis [32]. Compounds that inhibit apicoplast replication and protein expression affect the parasites only gradually: defects in apicoplast division and segregation are seen and the cells undergo “delayed death,” after several cell divisions [33–35].

Brucei MRPA), γ-glutamylcysteine synthetase, and glutathione synthetase was detected [98]. Glutathione synthetase and γ-glutamylcysteine synthetase are enzymes on the trypanothione synthesis pathway, and MRPA/PGPA exports antimonials and arsenicals as conjugates with trypanothione. Using the same gene array with RNA from methotrexate-resistant cells, increased expressions of the target (dihydrofolate reductase) and pteridine reductase and S-adenosylmethionine synthase were found [98]. Using a different mini-array containing all Leishmania genes encoding ABC proteins, three were found to be overexpressed in antimony-resistant cells [99].

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