Effects of microtubule inhibitors on protein synthesis in Plasmodium falciparum.
At low concentrations, both isomers of tubulozole (C, T) inhibit Plasmodium falciparum but only tubulozole C inhibits mammalian cells. Since tubulozole C prevents polymerization of mammalian tubulin whereas tubulozole T does not, the antimalarial action of tubulozoles may not involve microtubules. The present study concerns the inhibition of parasite protein synthesis by the tubulozoles. While tubulozoles took 3-4 h to kill parasites in erythrocytic culture, they inhibited protein synthesis within 10 min. The concentrations of the drug required were, however, too high for this to account for their antimalarial action. The microtubule inhibitor colcemid inhibited protein synthesis rapidly and at relevant concentrations, but vinblastine did not inhibit protein synthesis. Tubulozole T and colcemid inhibited protein synthesis posttranscriptionally since they had little effect on RNA synthesis. Analysis of labelled parasite proteins by two-dimensional gel electrophoresis showed that while it inhibited synthesis of most proteins to the same degree, tubulozole T super-inhibited the synthesis of certain proteins. This may cause its antimalarial effect at low concentrations.
Bell
A
A
Department of Structural Biology, University of Basel, Switzerland.
Wernli
B
B
Franklin
R M
RM
D000818:Animals; D000962:Antimalarials / Q000494:pharmacology*; D000970:Antineoplastic Agents / Q000494:pharmacology; D003513:Cycloheximide / Q000494:pharmacology; D003703:Demecolcine / Q000494:pharmacology*; D004148:Dioxolanes / Q000494:pharmacology*; D004351:Drug Resistance; D015180:Electrophoresis, Gel, Two-Dimensional / Q000379:methods; D004912:Erythrocytes / Q000502:physiology; D006801:Humans; D007700:Kinetics; D008715:Methionine / Q000378:metabolism; D008870:Microtubules / Q000187:drug effects*; D010963:Plasmodium falciparum / Q000187:drug effects / Q000378:metabolism*; D015800:Protozoan Proteins / Q000037:antagonists & inhibitors / Q000096:biosynthesis* / Q000302:isolation & purification; D016053:RNA, Protozoan / Q000096:biosynthesis; D014747:Vinblastine / Q000494:pharmacology*
D000962:Antimalarials; D000970:Antineoplastic Agents; D004148:Dioxolanes; D015800:Protozoan Proteins; D016053:RNA, Protozoan; C040422:tubulazole; D014747:Vinblastine; D003513:Cycloheximide; D008715:Methionine; D003703:Demecolcine