Antimalarial Benzoxaboroles Target Plasmodium falciparum Leucyl-tRNA Synthetase.
There is a need for new antimalarials, ideally with novel mechanisms of action. Benzoxaboroles have been shown to be active against bacteria, fungi, and trypanosomes. Therefore, we investigated the antimalarial activity and mechanism of action of 3-aminomethyl benzoxaboroles against Plasmodium falciparum Two 3-aminomethyl compounds, AN6426 and AN8432, demonstrated good potency against cultured multidrug-resistant (W2 strain) P. falciparum (50% inhibitory concentration [IC50] of 310 nM and 490 nM, respectively) and efficacy against murine Plasmodium berghei infection when administered orally once daily for 4 days (90% effective dose [ED90], 7.4 and 16.2 mg/kg of body weight, respectively). To characterize mechanisms of action, we selected parasites with decreased drug sensitivity by culturing with stepwise increases in concentration of AN6426. Resistant clones were characterized by whole-genome sequencing. Three generations of resistant parasites had polymorphisms in the predicted editing domain of the gene encoding a P. falciparum leucyl-tRNA synthetase (LeuRS; PF3D7_0622800) and in another gene (PF3D7_1218100), which encodes a protein of unknown function. Solution of the structure of the P. falciparum LeuRS editing domain suggested key roles for mutated residues in LeuRS editing. Short incubations with AN6426 and AN8432, unlike artemisinin, caused dose-dependent inhibition of [(14)C]leucine incorporation by cultured wild-type, but not resistant, parasites. The growth of resistant, but not wild-type, parasites was impaired in the presence of the unnatural amino acid norvaline, consistent with a loss of LeuRS editing activity in resistant parasites. In summary, the benzoxaboroles AN6426 and AN8432 offer effective antimalarial activity and act, at least in part, against a novel target, the editing domain of P. falciparum LeuRS.
Department of Medicine, University of California, San Francisco, California, USA Division of Infectious Diseases and Immunology, School of Public Health, University of California, Berkeley, California, USA.
Ebere
E
Sonoiki
European Molecular Biology Laboratory, Grenoble Outstation and Université Joseph Fourier, Centre National de la Recherche Scientifique and EMBL Unit of Virus Host-Cell Interactions, Grenoble, France.
Andres
A
Palencia
Department of Medicine, University of California, San Francisco, California, USA.
Denghui
D
Guo
Howard Hughes Medical Institute and the Department of Biochemistry and Biophysics, University of California, San Francisco, California, USA.
Vida
V
Ahyong
Anacor Pharmaceuticals, Inc., Palo Alto, California, USA.
Chen
C
Dong
Anacor Pharmaceuticals, Inc., Palo Alto, California, USA.
Xianfeng
X
Li
Anacor Pharmaceuticals, Inc., Palo Alto, California, USA.
Vincent S
VS
Hernandez
Anacor Pharmaceuticals, Inc., Palo Alto, California, USA.
Yong-Kang
YK
Zhang
Anacor Pharmaceuticals, Inc., Palo Alto, California, USA.
Wai
W
Choi
Department of Medicine, University of California, San Francisco, California, USA.
Jiri
J
Gut
Department of Medicine, University of California, San Francisco, California, USA.
Jennifer
J
Legac
Department of Natural Sciences and Mathematics, Dominican University of California, San Rafael, California, USA.
Roland
R
Cooper
Anacor Pharmaceuticals, Inc., Palo Alto, California, USA.
M R K
MR
Alley
Anacor Pharmaceuticals, Inc., Palo Alto, California, USA.
Yvonne R
YR
Freund
Howard Hughes Medical Institute and the Department of Biochemistry and Biophysics, University of California, San Francisco, California, USA.
Joseph
J
DeRisi
European Molecular Biology Laboratory, Grenoble Outstation and Université Joseph Fourier, Centre National de la Recherche Scientifique and EMBL Unit of Virus Host-Cell Interactions, Grenoble, France.
Stephen
S
Cusack
Department of Medicine, University of California, San Francisco, California, USA philip.rosenthal@ucsf.edu.
Philip J
PJ
Rosenthal
D000962:Antimalarials / Q000494:pharmacology*; D001896:Boron Compounds / Q000494:pharmacology; D004351:Drug Resistance / Q000187:drug effects; D020128:Inhibitory Concentration 50; D007935:Leucine-tRNA Ligase / Q000378:metabolism*; D016778:Malaria, Falciparum / Q000188:drug therapy* / Q000469:parasitology; D010963:Plasmodium falciparum / Q000187:drug effects* / Q000378:metabolism
C000621309:AN6426; D000962:Antimalarials; D001896:Boron Compounds; D007935:Leucine-tRNA Ligase