INHIBITION OF PLASMODIUM-FALCIPARUM PROTEIN-SYNTHESIS - TARGETING THEPLASTID-LIKE ORGANELLE WITH THIOSTREPTON

The human malaria parasite Plasmodium falciparum has two extrachromoso mal DNAs associated with organelles whose function is unclear. Both ge nomes encode ribosomal RNAs (rRNAs) that are distinct from the nuclear -encoded rRNAs. Secondary structure analysis of all the P. falciparum rRNAs indicates that only the large subunit (LSU) rRNA encoded by the plastid-like genome is the target for thiostrepton. Indeed we find tha t thiostrepton inhibits growth of the parasite in the micromolar range which is 10-fold below concentrations with observable effects on tota l protein synthesis. me have further examined selective effects of thi ostrepton on the plastid function by comparing differential effects of the drug on cytoplasmic and organellar encoded transcripts. Treatment with either thiostrepton or rifampin, an inhibitor of organellar and eubacterial RNA polymerase, both showed disappearance of organellar-en coded RNA transcripts within 6 h of treatment while transcripts of a n uclear-encoded mRNA remained constant for at least 8 h of treatment. H ence, we show a selective effect on organelle function that is suggest ive of interference in the protein synthesis apparatus of the plastid. Sensitivity of P. falciparum to thiostrepton confirms that the plasti d-like genome is essential for the erythrocytic cycle and presents a n ovel therapeutic site for this class of antibiotics.