Selective and specific inhibition of the plasmodium falciparum lysyl-tRNA synthetase by the fungal secondary metabolite cladosporin.
With renewed calls for malaria eradication, next-generation antimalarials need be active against drug-resistant parasites and efficacious against both liver- and blood-stage infections. We screened a natural product library to identify inhibitors of Plasmodium falciparum blood- and liver-stage proliferation. Cladosporin, a fungal secondary metabolite whose target and mechanism of action are not known for any species, was identified as having potent, nanomolar, antiparasitic activity against both blood and liver stages. Using postgenomic methods, including a yeast deletion strains collection, we show that cladosporin specifically inhibits protein synthesis by directly targeting P. falciparum cytosolic lysyl-tRNA synthetase. Further, cladosporin is >100-fold more potent against parasite lysyl-tRNA synthetase relative to the human enzyme, which is conferred by the identity of two amino acids within the enzyme active site. Our data indicate that lysyl-tRNA synthetase is an attractive, druggable, antimalarial target that can be selectively inhibited.
Novartis Institutes for BioMedical Research, Novartis Pharma AG, Forum 1 Novartis Campus, Basel, Switzerland. dominic.hoepfner@novartis.com
Dominic
D
Hoepfner
Case W
CW
McNamara
Chek Shik
CS
Lim
Christian
C
Studer
Ralph
R
Riedl
Thomas
T
Aust
Susan L
SL
McCormack
David M
DM
Plouffe
Stephan
S
Meister
Sven
S
Schuierer
Uwe
U
Plikat
Nicole
N
Hartmann
Frank
F
Staedtler
Simona
S
Cotesta
Esther K
EK
Schmitt
Frank
F
Petersen
Frantisek
F
Supek
Richard J
RJ
Glynne
John A
JA
Tallarico
Jeffrey A
JA
Porter
Mark C
MC
Fishman
Christophe
C
Bodenreider
Thierry T
TT
Diagana
N Rao
NR
Movva
Elizabeth A
EA
Winzeler
D000962:Antimalarials / Q000302:isolation & purification / Q000494:pharmacology*; D002460:Cell Line; D004353:Drug Evaluation, Preclinical / Q000379:methods; D004791:Enzyme Inhibitors / Q000302:isolation & purification / Q000494:pharmacology*; D005658:Fungi / Q000737:chemistry*; D006801:Humans; D020128:Inhibitory Concentration 50; D049934:Isocoumarins / Q000302:isolation & purification / Q000494:pharmacology*; D008250:Lysine-tRNA Ligase / Q000037:antagonists & inhibitors*; D021261:Parasitic Sensitivity Tests; D010963:Plasmodium falciparum / Q000187:drug effects / Q000201:enzymology*; D014176:Protein Biosynthesis / Q000187:drug effects; D015800:Protozoan Proteins / Q000037:antagonists & inhibitors
D000962:Antimalarials; D004791:Enzyme Inhibitors; D049934:Isocoumarins; D015800:Protozoan Proteins; C000488:cladosporin; D008250:Lysine-tRNA Ligase