Selective inhibition of apicoplast tryptophanyl-tRNA synthetase causes delayed death in Plasmodium falciparum.
The malaria parasite Plasmodium falciparum relies on efficient protein translation. An essential component of translation is the tryptophanyl-tRNA synthetase (TrpRS) that charges tRNA(trp). Here we characterise two isoforms of TrpRS in Plasmodium; one eukaryotic type localises to the cytosol and a bacterial type localises to the remnant plastid (apicoplast). We show that the apicoplast TrpRS aminoacylates bacterial tRNA(trp) while the cytosolic TrpRS charges eukaryotic tRNA(trp). An inhibitor of bacterial TrpRSs, indolmycin, specifically inhibits aminoacylation by the apicoplast TrpRS in vitro, and inhibits ex vivo Plasmodium parasite growth, killing parasites with a delayed death effect characteristic of apicoplast inhibitors. Indolmycin treatment ablates apicoplast inheritance and is rescuable by addition of the apicoplast metabolite isopentenyl pyrophosphate (IPP). These data establish that inhibition of an apicoplast housekeeping enzyme leads to loss of the apicoplast and this is sufficient for delayed death. Apicoplast TrpRS is essential for protein translation and is a promising, specific antimalarial target.
Department of Biochemistry and Molecular Biology, Bio21 Molecular Science and Biotechnology Institute, The University of Melbourne, Victoria 3010, Australia.
Charisse Flerida A
CF
Pasaje
Department of Biochemistry and Molecular Biology, Bio21 Molecular Science and Biotechnology Institute, The University of Melbourne, Victoria 3010, Australia.
Vanessa
V
Cheung
Department of Biochemistry and Molecular Biology, Bio21 Molecular Science and Biotechnology Institute, The University of Melbourne, Victoria 3010, Australia.
Kit
K
Kennedy
Department of Biochemistry and Molecular Biology, Bio21 Molecular Science and Biotechnology Institute, The University of Melbourne, Victoria 3010, Australia.
Erin E
EE
Lim
Medicinal Chemistry, Monash Institute of Pharmaceutical Sciences, Monash University, 399 Royal Parade, Parkville, 3052 Victoria, Australia.
Jonathan B
JB
Baell
Department of Biochemistry and Molecular Biology, Bio21 Molecular Science and Biotechnology Institute, The University of Melbourne, Victoria 3010, Australia.
Michael D W
MD
Griffin
Department of Biochemistry and Molecular Biology, Bio21 Molecular Science and Biotechnology Institute, The University of Melbourne, Victoria 3010, Australia.
Stuart A
SA
Ralph
D000962:Antimalarials / Q000494:pharmacology*; D063546:Apicoplasts / Q000187:drug effects / Q000201:enzymology; D019295:Computational Biology; D003600:Cytosol / Q000378:metabolism; D019143:Evolution, Molecular; D005816:Genetic Complementation Test; D049452:Green Fluorescent Proteins / Q000378:metabolism; D007211:Indoles / Q000737:chemistry; D020128:Inhibitory Concentration 50; D010802:Phylogeny; D010957:Plasmids / Q000378:metabolism; D010963:Plasmodium falciparum / Q000187:drug effects* / Q000201:enzymology; D014176:Protein Biosynthesis; D015800:Protozoan Proteins / Q000037:antagonists & inhibitors*; D014364:Tryptophan / Q000737:chemistry; D014369:Tryptophan-tRNA Ligase / Q000037:antagonists & inhibitors*
D000962:Antimalarials; D007211:Indoles; D015800:Protozoan Proteins; D049452:Green Fluorescent Proteins; D014364:Tryptophan; D014369:Tryptophan-tRNA Ligase; C001447:indolmycin