title: Discovery of Novel Oral Protein Synthesis Inhibitors of Mycobacterium tuberculosis That Target Leucyl-tRNA Synthetase.
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.
authors: European Molecular Biology Laboratory, Grenoble, France.
authors: Andrés
authors: A
authors: Palencia
authors: Anacor Pharmaceuticals, Palo Alto, California, USA.
authors: Xianfeng
authors: X
authors: Li
authors: Anacor Pharmaceuticals, Palo Alto, California, USA.
authors: Wei
authors: W
authors: Bu
authors: Anacor Pharmaceuticals, Palo Alto, California, USA.
authors: Wai
authors: W
authors: Choi
authors: Anacor Pharmaceuticals, Palo Alto, California, USA.
authors: Charles Z
authors: CZ
authors: Ding
authors: Anacor Pharmaceuticals, Palo Alto, California, USA.
authors: Eric E
authors: EE
authors: Easom
authors: Anacor Pharmaceuticals, Palo Alto, California, USA.
authors: Lisa
authors: L
authors: Feng
authors: Anacor Pharmaceuticals, Palo Alto, California, USA.
authors: Vincent
authors: V
authors: Hernandez
authors: Anacor Pharmaceuticals, Palo Alto, California, USA.
authors: Paul
authors: P
authors: Houston
authors: Anacor Pharmaceuticals, Palo Alto, California, USA.
authors: Liang
authors: L
authors: Liu
authors: Anacor Pharmaceuticals, Palo Alto, California, USA.
authors: Maliwan
authors: M
authors: Meewan
authors: Anacor Pharmaceuticals, Palo Alto, California, USA.
authors: Manisha
authors: M
authors: Mohan
authors: Anacor Pharmaceuticals, Palo Alto, California, USA.
authors: Fernando L
authors: FL
authors: Rock
authors: Anacor Pharmaceuticals, Palo Alto, California, USA.
authors: Holly
authors: H
authors: Sexton
authors: Anacor Pharmaceuticals, Palo Alto, California, USA.
authors: Suoming
authors: S
authors: Zhang
authors: Anacor Pharmaceuticals, Palo Alto, California, USA.
authors: Yasheen
authors: Y
authors: Zhou
authors: Institute for Tuberculosis Research, University of Illinois at Chicago, Chicago, Illinois, USA.
authors: Baojie
authors: B
authors: Wan
authors: Institute for Tuberculosis Research, University of Illinois at Chicago, Chicago, Illinois, USA.
authors: Yuehong
authors: Y
authors: Wang
authors: Institute for Tuberculosis Research, University of Illinois at Chicago, Chicago, Illinois, USA.
authors: Scott G
authors: SG
authors: Franzblau
authors: Mycobacteria Research Laboratories, Department of Microbiology, Immunology and Pathology, Colorado State University, Fort Collins, Colorado, USA.
authors: Lisa
authors: L
authors: Woolhiser
authors: Mycobacteria Research Laboratories, Department of Microbiology, Immunology and Pathology, Colorado State University, Fort Collins, Colorado, USA.
authors: Veronica
authors: V
authors: Gruppo
authors: Mycobacteria Research Laboratories, Department of Microbiology, Immunology and Pathology, Colorado State University, Fort Collins, Colorado, USA.
authors: Anne J
authors: AJ
authors: Lenaerts
authors: TB Discovery Research, Infectious Disease Research Institute, Seattle, Washington, USA.
authors: Theresa
authors: T
authors: O'Malley
authors: TB Discovery Research, Infectious Disease Research Institute, Seattle, Washington, USA.
authors: Tanya
authors: T
authors: Parish
authors: Global Alliance for TB Drug Development, New York, New York, USA.
authors: Christopher B
authors: CB
authors: Cooper
authors: Global Alliance for TB Drug Development, New York, New York, USA.
authors: M Gerard
authors: MG
authors: Waters
authors: Global Alliance for TB Drug Development, New York, New York, USA.
authors: Zhenkun
authors: Z
authors: Ma
authors: Department of Biochemistry and Biophysics, Texas A&M University, College Station, Texas, USA.
authors: Thomas R
authors: TR
authors: Ioerger
authors: Department of Biochemistry and Biophysics, Texas A&M University, College Station, Texas, USA.
authors: James C
authors: JC
authors: Sacchettini
authors: Tres Cantos Medicines Development Campus, GlaxoSmithKline, Tres Cantos, Spain.
authors: Joaquín
authors: J
authors: Rullas
authors: Tres Cantos Medicines Development Campus, GlaxoSmithKline, Tres Cantos, Spain.
authors: Iñigo
authors: I
authors: Angulo-Barturen
authors: Tres Cantos Medicines Development Campus, GlaxoSmithKline, Tres Cantos, Spain.
authors: Esther
authors: E
authors: Pérez-Herrán
authors: Tres Cantos Medicines Development Campus, GlaxoSmithKline, Tres Cantos, Spain.
authors: Alfonso
authors: A
authors: Mendoza
authors: Tres Cantos Medicines Development Campus, GlaxoSmithKline, Tres Cantos, Spain.
authors: David
authors: D
authors: Barros
authors: European Molecular Biology Laboratory, Grenoble, France.
authors: Stephen
authors: S
authors: Cusack
authors: Anacor Pharmaceuticals, Palo Alto, California, USA.
authors: Jacob J
authors: JJ
authors: Plattner
authors: Anacor Pharmaceuticals, Palo Alto, California, USA dickon_alley@mac.com.
authors: M R K
authors: MR
authors: Alley
mesh_terms: D000284:Administration, Oral; D000818:Animals; D000995:Antitubercular Agents / Q000008:administration & dosage / Q000737:chemistry / Q000493:pharmacokinetics / Q000494:pharmacology*; D004195:Disease Models, Animal; D004353:Drug Evaluation, Preclinical / Q000379:methods; D005260:Female; D006801:Humans; D007935:Leucine-tRNA Ligase / Q000037:antagonists & inhibitors* / Q000737:chemistry / Q000235:genetics; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D008815:Mice, Inbred Strains; D008826:Microbial Sensitivity Tests; D020102:Mycobacterium smegmatis / Q000187:drug effects / Q000235:genetics; D009169:Mycobacterium tuberculosis / Q000187:drug effects* / Q000235:genetics; D011500:Protein Synthesis Inhibitors / Q000008:administration & dosage / Q000737:chemistry / Q000493:pharmacokinetics / Q000494:pharmacology*; D013329:Structure-Activity Relationship; D014376:Tuberculosis / Q000188:drug therapy; D014709:Vero Cells
chemical_list: D000995:Antitubercular Agents; D011500:Protein Synthesis Inhibitors; D007935:Leucine-tRNA Ligase