title: Discovery of a potent benzoxaborole-based anti-pneumococcal agent targeting leucyl-tRNA synthetase.
abstract: Streptococcus pneumoniae causes bacterial pneumonia with high mortality and morbidity. The emergency of multidrug-resistant bacteria threatens the treatment of the disease. Leucyl-tRNA synthetase (LeuRS) plays an essential role in cellular translation and is an attractive drug target for antimicrobial development. Here we report the compound ZCL039, a benzoxaborole-based derivative of AN2690, as a potent anti-pneumococcal agent that inhibits S. pneumoniae LeuRS (SpLeuRS) activity. We show using kinetic, biochemical analyses combined with the crystal structure of ZCL039-AMP in complex with the separated SpLeuRS editing domain, that ZCL039 binds to the LeuRS editing active site which requires the presence of tRNA(Leu), and employs an uncompetitive inhibition mechanism. Further docking models establish that ZCL039 clashes with the eukaryal/archaeal specific insertion I4ae helix within editing domains. These findings demonstrate the potential of benzoxaboroles as effective LeuRS inhibitors for pneumococcus infection therapy, and provide future structure-guided drug design and optimization.
authors: 1] State Key Laboratory of Molecular Biology, Center for RNA research, Institute of Biochemistry and Cell Biology, Shanghai Institutes for Biological Sciences, The Chinese Academy of Sciences, Shanghai 200031, China [2].
authors: Qing-Hua
authors: QH
authors: Hu
authors: Ru-Juan
authors: RJ
authors: Liu
authors: Zhi-Peng
authors: ZP
authors: Fang
authors: Jiong
authors: J
authors: Zhang
authors: Ying-Ying
authors: YY
authors: Ding
authors: Min
authors: M
authors: Tan
authors: Meng
authors: M
authors: Wang
authors: Wei
authors: W
authors: Pan
authors: Hu-Chen
authors: HC
authors: Zhou
authors: En-Duo
authors: ED
authors: Wang
mesh_terms: D000900:Anti-Bacterial Agents / Q000008:administration & dosage; D017209:Apoptosis / Q000187:drug effects / Q000502:physiology; D001896:Boron Compounds / Q000008:administration & dosage*; D019086:Bridged Bicyclo Compounds, Heterocyclic / Q000008:administration & dosage*; D002470:Cell Survival / Q000187:drug effects / Q000502:physiology; D016503:Drug Delivery Systems / Q000379:methods; D007935:Leucine-tRNA Ligase / Q000037:antagonists & inhibitors*; D013296:Streptococcus pneumoniae / Q000187:drug effects* / Q000502:physiology*
chemical_list: D000900:Anti-Bacterial Agents; D001896:Boron Compounds; D019086:Bridged Bicyclo Compounds, Heterocyclic; D007935:Leucine-tRNA Ligase; C512998:tavaborole
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