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Obafluorin (OB), a natural \u03b2\u2010lactone antibiotic, is a covalent inhibitor of threonyl\u2010tRNA synthetase (ThrRS), but the high conservation of the active site between prokaryote and eukaryote ThrRSs results in minimal selectivity, hindering the therapeutic potential of OB. Here, we report a structure dynamics\u2010based design strategy that transforms OB into a selective antibacterial agent. OB inhibits human and bacterial ThrRSs with nearly equal potency due to identical binding modes. The nitrophenyl moiety of OB is proposed as a \u2018kinetic sensor\u2019 that discriminates between sensitive and resistant ThrRS paralogs. Guided by this insight, we designed a series of OB analogs through rational modification of this moiety. Among them, OB\u2010D4 bearing a\n                    <jats:italic>para<\/jats:italic>\n                    \u2010methoxyphenyl group in place of the nitrophenyl group, exhibited a 241\u2010fold selectivity for bacterial over human ThrRS, along with a markedly improved safety profile with minimal cytotoxicity. In a murine skin infection model, OB\u2010D4 effectively eradicated pathogens, resolving inflammation, and promoting wound healing. Together, this work establishes a \u2018kinetic sensor\u2019 strategy for achieving species selectivity, turning a fundamental challenge in drug discovery\u2010high active\u2010site conservation\u2014into an exploitable opportunity based on dynamic differences.\n                  <\/jats:p>","DOI":"10.1002\/anie.5509036","type":"journal-article","created":{"date-parts":[[2026,9,1]],"date-time":"2026-09-01T10:56:42Z","timestamp":1788260202000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Leveraging Protein Dynamics for Selective Inhibition of Threonyl\u2010tRNA Synthetase by Obafluorin Analogs"],"prefix":"10.1002","volume":"65","author":[{"given":"Zilu","family":"Wang","sequence":"first","affiliation":[{"name":"State Key Laboratory of Chemical Biology Shanghai Institute of Organic Chemistry University of Chinese Academy of Sciences  Shanghai China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zhengxuan","family":"Zhang","sequence":"additional","affiliation":[{"name":"State Key Laboratory of Chemical Biology Shanghai Institute of Organic Chemistry University of Chinese Academy of Sciences  Shanghai China"},{"name":"School of Physical Science and Technology ShanghaiTech University  Shanghai China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mingyu","family":"Xia","sequence":"additional","affiliation":[{"name":"State Key Laboratory of Chemical Biology Shanghai Institute of Organic Chemistry University of Chinese Academy of Sciences  Shanghai China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Min","family":"Fang","sequence":"additional","affiliation":[{"name":"State Key Laboratory of Chemical Biology Shanghai Institute of Organic Chemistry University of Chinese Academy of Sciences  Shanghai China"},{"name":"School of Materials and Chemistry Shanghai For Science and Technology University  Shanghai China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Haoran","family":"Xu","sequence":"additional","affiliation":[{"name":"State Key Laboratory of Chemical Biology Shanghai Institute of Organic Chemistry University of Chinese Academy of Sciences  Shanghai China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hang","family":"Qiao","sequence":"additional","affiliation":[{"name":"State Key Laboratory of Chemical Biology Shanghai Institute of Organic Chemistry University of Chinese Academy of Sciences  Shanghai China"},{"name":"Interdisciplinary Research Center on Biology and Chemistry Shanghai Institute of Organic Chemistry Chinese Academy of Sciences  Shanghai China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Wenping","family":"Ding","sequence":"additional","affiliation":[{"name":"State Key Laboratory of Chemical Biology Shanghai Institute of Organic Chemistry University of Chinese Academy of Sciences  Shanghai China"},{"name":"School of Life Science &amp; Biotechnology Shanghai Jiao Tong University  Shanghai China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jiancheng","family":"Huang","sequence":"additional","affiliation":[{"name":"State Key Laboratory of Chemical Biology Shanghai Institute of Organic Chemistry University of Chinese Academy of Sciences  Shanghai China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Guozheng","family":"Li","sequence":"additional","affiliation":[{"name":"State Key Laboratory of Chemical Biology Shanghai Institute of Organic Chemistry University of Chinese Academy of Sciences  Shanghai China"},{"name":"Key Laboratory of Structure\u2010Based Drugs Design and Discovery of Ministry of Education Shenyang Pharmaceutical University  Shenyang China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ke","family":"Luo","sequence":"additional","affiliation":[{"name":"State Key Laboratory of Chemical Biology Shanghai Institute of Organic Chemistry University of Chinese Academy of Sciences  Shanghai China"},{"name":"Key Laboratory of Glyco\u2010drug Research of Zhejiang Province School of Chemistry and Materials Science Hangzhou Institute for Advanced Study University of Chinese Academy of Sciences  Hangzhou China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8835-8012","authenticated-orcid":false,"given":"Wen","family":"Liu","sequence":"additional","affiliation":[{"name":"State Key Laboratory of Chemical Biology Shanghai Institute of Organic Chemistry University of Chinese Academy of Sciences  Shanghai China"},{"name":"School of Life Science &amp; 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