THE APICOPLAST--A TARGET FOR PARASITICIDAL CHEMOTHERAPY

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The phylum Apicomplexa includes many human pathogens, such as Plasmodium (the causative agent of malaria), Toxoplasma and Cryptosporidium (important opportunistic parasites associated with AIDS). Widespread drug-resistance and the poor tolerance of treatments available have lent new urgency to the development of novel chemotherapeutic strategies for these parasites. The discovery that these organisms harbor a plastid which is essential for their survival has therefore produced considerable interest. Several antibiotics that are normally effective only against prokaryotic organisms (including macrolides and fluoroquinolones) exhibit activity against Toxoplasma gondii and other apicomplexans, and several lines of argument suggest that these compounds target apicoplast functions. The objectives of this proposal are to test this hypothesis, by: (1) Examining the kinetics of death observed in rifamycin antibiotics (thought to inhibit the plastid-encoded RNA polymerase), and developing T. gondii mutants resistant to rifamycins. (2) Identifying and characterizing nuclear-encoded plastid topoisomerases (the probable target of fluoroquinolone antibiotics), using a combination of bioinformatic, biochemical, and genetic approaches.