title: Identification of an anti-TB compound targeting the tyrosyl-tRNA synthetase.
abstract: OBJECTIVE
  Drug-resistant Mycobacterium tuberculosis poses a great threat to human health. Tyrosyl-tRNA synthetase (TyrRS) is one of the aminoacyl tRNA synthetases that catalyse the attachment of amino acids to their cognate tRNAs and are essential for protein synthesis. There are several distinctive differences between bacterial and human TyrRS and therefore it could be a potential target for developing antimicrobial agents. This study aimed to identify a new anti-TB agent targeting M. tuberculosis TyrRS (MtTyrRS).
  
  
  METHODS
  We first used Mycobacterium smegmatis for a phenotypic screening of 20 000 compounds. The hit compounds were then screened with MtTyrRS. The interaction between hit compound IMB-T130 and the target protein was analysed by surface plasmon resonance (SPR) assay and molecular docking experiments. The target of IMB-T130 was further confirmed by the overexpression of the target protein. The antibacterial activity of IMB-T130 against various standard and clinical drug-resistant M. tuberculosis strains was evaluated using the microplate Alamar blue assay.
  
  
  RESULTS
  Compound IMB-T130 was identified as a hit compound that inhibits the growth of M. smegmatis and the in vitro activity of MtTyrRS. The interaction between IMB-T130 and MtTyrRS was confirmed by SPR assay and molecular docking analysis. The higher MIC for a strain overexpressing the target protein also suggests that MtTyrRS is likely to be the target of IMB-T130. IMB-T130 shows excellent anti-TB activity and low cytotoxicity.
  
  
  CONCLUSIONS
  IMB-T130 inhibits the growth of MDR-TB and XDR-TB by targeting MtTyrRS. Because of its low cytotoxicity against mammalian cells, IMB-T130 is a promising new agent against drug-resistant M. tuberculosis.
authors.affiliation: Institute of Medicinal Biotechnology, Peking Union Medical College and Chinese Academy of Medical Sciences, Beijing 100050, China.
authors.forename: Ningyu
authors.initials: N
authors.lastname: Zhu
authors.affiliation: State Key Laboratory of Bioactive Substances and Function of Natural Medicine, Institute of Materia Medica, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100050, China.
authors.forename: Yuan
authors.initials: Y
authors.lastname: Lin
authors.affiliation: Institute of Medicinal Biotechnology, Peking Union Medical College and Chinese Academy of Medical Sciences, Beijing 100050, China.
authors.forename: Dongsheng
authors.initials: D
authors.lastname: Li
authors.affiliation: Institute of Medicinal Biotechnology, Peking Union Medical College and Chinese Academy of Medical Sciences, Beijing 100050, China.
authors.forename: Nana
authors.initials: N
authors.lastname: Gao
authors.affiliation: Institute of Medicinal Biotechnology, Peking Union Medical College and Chinese Academy of Medical Sciences, Beijing 100050, China.
authors.forename: Chang
authors.initials: C
authors.lastname: Liu
authors.affiliation: Institute of Medicinal Biotechnology, Peking Union Medical College and Chinese Academy of Medical Sciences, Beijing 100050, China.
authors.forename: Xuefu
authors.initials: X
authors.lastname: You
authors.affiliation: Institute of Medicinal Biotechnology, Peking Union Medical College and Chinese Academy of Medical Sciences, Beijing 100050, China State Key Laboratory of Bioactive Substances and Function of Natural Medicine, Institute of Materia Medica, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100050, China.
authors.forename: Jiandong
authors.initials: J
authors.lastname: Jiang
authors.affiliation: Institute of Medicinal Biotechnology, Peking Union Medical College and Chinese Academy of Medical Sciences, Beijing 100050, China.
authors.forename: Wei
authors.initials: W
authors.lastname: Jiang
authors.affiliation: Institute of Medicinal Biotechnology, Peking Union Medical College and Chinese Academy of Medical Sciences, Beijing 100050, China sisyimb@hotmail.com.
authors.forename: Shuyi
authors.initials: S
authors.lastname: Si
mesh_terms: D000995:Antitubercular Agents / Q000302:isolation & purification* / Q000494:pharmacology* / Q000633:toxicity; D002460:Cell Line; D002470:Cell Survival / Q000187:drug effects; D004353:Drug Evaluation, Preclinical; D006801:Humans; D008826:Microbial Sensitivity Tests; D062105:Molecular Docking Simulation; D020102:Mycobacterium smegmatis / Q000187:drug effects* / Q000201:enzymology*; D020349:Surface Plasmon Resonance; D014448:Tyrosine-tRNA Ligase / Q000037:antagonists & inhibitors*
chemical_list: D000995:Antitubercular Agents; D014448:Tyrosine-tRNA Ligase
keywords: Mycobacterium tuberculosis; SPR assay; anti-tuberculosis drug screen; molecular docking