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Antimicrob Agents Chemother. 2016 Sep 23;60(10):6271-80. doi: 10.1128/AAC.01339-16. Print 2016 Oct.

Discovery of Novel Oral Protein Synthesis Inhibitors of Mycobacterium tuberculosis That Target Leucyl-tRNA Synthetase.

Author information

1
European Molecular Biology Laboratory, Grenoble, France.
2
Anacor Pharmaceuticals, Palo Alto, California, USA.
3
Institute for Tuberculosis Research, University of Illinois at Chicago, Chicago, Illinois, USA.
4
Mycobacteria Research Laboratories, Department of Microbiology, Immunology and Pathology, Colorado State University, Fort Collins, Colorado, USA.
5
TB Discovery Research, Infectious Disease Research Institute, Seattle, Washington, USA.
6
Global Alliance for TB Drug Development, New York, New York, USA.
7
Department of Biochemistry and Biophysics, Texas A&M University, College Station, Texas, USA.
8
Tres Cantos Medicines Development Campus, GlaxoSmithKline, Tres Cantos, Spain.
9
Anacor Pharmaceuticals, Palo Alto, California, USA dickon_alley@mac.com.

Abstract

The recent development and spread of extensively drug-resistant and totally drug-resistant resistant (TDR) strains of Mycobacterium tuberculosis highlight the need for new antitubercular drugs. Protein synthesis inhibitors have played an important role in the treatment of tuberculosis (TB) starting with the inclusion of streptomycin in the first combination therapies. Although parenteral aminoglycosides are a key component of therapy for multidrug-resistant TB, the oxazolidinone linezolid is the only orally available protein synthesis inhibitor that is effective against TB. Here, we show that small-molecule inhibitors of aminoacyl-tRNA synthetases (AARSs), which are known to be excellent antibacterial protein synthesis targets, are orally bioavailable and effective against M. tuberculosis in TB mouse infection models. We applied the oxaborole tRNA-trapping (OBORT) mechanism, which was first developed to target fungal cytoplasmic leucyl-tRNA synthetase (LeuRS), to M. tuberculosis LeuRS. X-ray crystallography was used to guide the design of LeuRS inhibitors that have good biochemical potency and excellent whole-cell activity against M. tuberculosis Importantly, their good oral bioavailability translates into in vivo efficacy in both the acute and chronic mouse models of TB with potency comparable to that of the frontline drug isoniazid.

PMID:
27503647
PMCID:
PMC5038265
DOI:
10.1128/AAC.01339-16
[Indexed for MEDLINE]
Free PMC Article

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