Antimalarial Benzoxaboroles Target Plasmodium falciparum Leucyl-tRNA Synthetase.

Authors

Ebere Sonoiki, Department of Medicine, University of California, San Francisco
Andres Palencia, European Molecular Biology Laboratory, Grenoble Outstation and Université Joseph Fourier, Centre National de la Recherche Scientifique and EMBL Unit of Virus Host-Cell Interactions
Denghui Guo, Department of Medicine, University of California, San FranciscoFollow
Vida Ahyong, Howard Hughes Medical Institute and the Department of Biochemistry and Biophysics, University of California, San FranciscoFollow
Chen Dong, Anacor Pharmaceuticals, Inc.
Xianfeng Li, Anacor Pharmaceuticals, Inc.
Vincent S. Hernandez, Anacor Pharmaceuticals, Inc.
Yong-Kang Zhang, Anacor Pharmaceuticals, Inc.
Wai Choi, Anacor Pharmaceuticals, Inc.
Jiri Gut, Department of Medicine, University of California, San FranciscoFollow
Jennifer Legac, Department of Medicine, University of California, San FranciscoFollow
Roland A. Cooper, Department of Natural Sciences and Mathematics, Dominican University of CaliforniaFollow
M. R. K. Alley, Anacor Pharmaceuticals, Inc.Follow
Yvonne R. Freund, Anacor Pharmaceuticals, Inc.Follow
Joseph DeRisi, Howard Hughes Medical Institute and the Department of Biochemistry and Biophysics, University of California, San FranciscoFollow
Stephen Cusack, European Molecular Biology Laboratory, Grenoble Outstation and Université Joseph Fourier, Centre National de la Recherche Scientifique and EMBL Unit of Virus Host-Cell Interactions
Philip J. Rosenthal, Department of Medicine, University of California, San FranciscoFollow

Department

Natural Sciences and Mathematics

Document Type

Article

Source

Antimicrobial Agents and Chemotherapy

Publication Date

8-1-2016

ISSN

1098-6596

Volume

60

Issue

8

First Page

4886

Last Page

4895

Abstract

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.

PubMed ID

27270277

Rights

Copyright © 2016, American Society for Microbiology. All Rights Reserved.