title: The effects of anti-bacterials on the malaria parasite Plasmodium falciparum.
abstract: Many anti-bacterial drugs inhibit growth of malaria parasites by targeting their bacterium-derived endosymbiotic organelles, the mitochondrion and plastid. Several of these drugs are either in use or being developed as therapeutics or prophylactics, so it is paramount to understand more about their target of action and modality. To this end, we measured in vitro growth and visualized nuclear division and the development of the mitochondrion and apicoplast in Plasmodium falciparum treated with five drugs targeting bacterial housekeeping pathways. This revealed two distinct classes of drug effect. Ciprofloxacin, rifampicin, and thiostrepton had an immediate effect: slowing parasite growth, retarding organellar development and preventing nuclear division. Classic delayed-death, in which the drug has no apparent effect until division and reinvasion of a new host by the daughter merozoites, was only observed for two drugs: clindamycin and tetracycline. These cells had apparently normal division and segregation of organelles in the first cycle but severe defects in apicoplast growth, subtle changes in the mitochondrion and a failure to complete cytokinesis during the second cycle. In two cases, the drug response in P. falciparum directly conflicted with reported responses for the related parasite Toxoplasma gondii, suggesting significant differences in apicoplast biology between the two parasites.
authors.affiliation: Plant Cell Biology Research Centre, School of Botany, University of Melbourne, Parkville, Victoria 3010, Australia.
authors.forename: Christopher Dean
authors.initials: CD
authors.lastname: Goodman
authors.forename: Vanessa
authors.initials: V
authors.lastname: Su
authors.forename: Geoffrey I
authors.initials: GI
authors.lastname: McFadden
mesh_terms: D000818:Animals; D000900:Anti-Bacterial Agents / Q000494:pharmacology*; D002478:Cells, Cultured; D002939:Ciprofloxacin / Q000494:pharmacology; D002981:Clindamycin / Q000494:pharmacology; D004261:DNA Replication / Q000187:drug effects; D016778:Malaria, Falciparum / Q000188:drug therapy / Q000378:metabolism; D010963:Plasmodium falciparum / Q000187:drug effects* / Q000254:growth & development; D014176:Protein Biosynthesis; D012293:Rifampin / Q000494:pharmacology; D013752:Tetracycline / Q000494:pharmacology; D013883:Thiostrepton / Q000494:pharmacology; D013997:Time Factors; D014158:Transcription, Genetic
chemical_list: D000900:Anti-Bacterial Agents; D002981:Clindamycin; D002939:Ciprofloxacin; D013752:Tetracycline; D013883:Thiostrepton; D012293:Rifampin