A mevalonate bypass system facilitates elucidation of plastid biology in malaria parasites

Russell P. Swift, Krithika Rajaram, Hans B. Liu, Amanda Dziedzic, Anne E. Jedlicka, Aleah D. Roberts, Krista A. Matthews, Hugo Jhun, Namandje N. Bumpus, Shivendra G. Tewari, Anders Wallqvist, Sean T. Prigge

Research output: Contribution to journalArticle

Abstract

Malaria parasites rely on a plastid organelle for survival during the blood stages of infection. However, the entire organelle is dispensable as long as the isoprenoid precursor, isopentenyl pyrophosphate (IPP), is supplemented in the culture medium. We engineered parasites to produce isoprenoid precursors from a mevalonate-dependent pathway, creating a parasite line that replicates normally after the loss of the apicoplast organelle. We show that carbon-labeled mevalonate is specifically incorporated into isoprenoid products, opening new avenues for researching this essential class of metabolites in malaria parasites. We also show that essential apicoplast proteins, such as the enzyme target of the drug fosmidomycin, can be deleted in this mevalonate bypass parasite line, providing a new method to determine the roles of other important apicoplast-resident proteins. Several antibacterial drugs kill malaria parasites by targeting basic processes, such as transcription, in the organelle. We used metabolomic and transcriptomic methods to characterize parasite metabolism after azithromycin treatment triggered loss of the apicoplast and found that parasite metabolism and the production of apicoplast proteins is largely unaltered. These results provide insight into the effects of apicoplast-disrupting drugs, several of which have been used to treat malaria infections in humans. Overall, the mevalonate bypass system provides a way to probe essential aspects of apicoplast biology and study the effects of drugs that target apicoplast processes.

Original languageEnglish (US)
Article numbere1008316
JournalPLoS pathogens
Volume16
Issue number2
DOIs
StatePublished - Jan 1 2020

ASJC Scopus subject areas

  • Parasitology
  • Microbiology
  • Immunology
  • Molecular Biology
  • Genetics
  • Virology

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  • Cite this

    Swift, R. P., Rajaram, K., Liu, H. B., Dziedzic, A., Jedlicka, A. E., Roberts, A. D., Matthews, K. A., Jhun, H., Bumpus, N. N., Tewari, S. G., Wallqvist, A., & Prigge, S. T. (2020). A mevalonate bypass system facilitates elucidation of plastid biology in malaria parasites. PLoS pathogens, 16(2), [e1008316]. https://doi.org/10.1371/journal.ppat.1008316