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While covalent SrtA inhibitors show therapeutic potential, existing compounds lack species selectivity. Through structure\u2010guided design, we developed\n                    <jats:bold>T10<\/jats:bold>\n                    , a covalent inhibitor selectively targeting\n                    <jats:italic>Streptococcus pyogenes<\/jats:italic>\n                    SrtA (\n                    <jats:italic>Sp<\/jats:italic>\n                    SrtA) over\n                    <jats:italic>Staphylococcus aureus<\/jats:italic>\n                    SrtA (\n                    <jats:italic>Sa<\/jats:italic>\n                    SrtA). Molecular docking revealed that shortening a \u201cC=C\u201d bond in lead compound\n                    <jats:bold>ML346<\/jats:bold>\n                    eliminated\n                    <jats:italic>Sa<\/jats:italic>\n                    SrtA inhibition due to steric hindrance from W194, while maintaining\n                    <jats:italic>Sp<\/jats:italic>\n                    SrtA binding. X\u2010ray crystallography confirmed\n                    <jats:bold>T10<\/jats:bold>\n                    \u2032s covalent modification of Cys208 in\n                    <jats:italic>Sp<\/jats:italic>\n                    SrtA.\n                    <jats:bold>T10<\/jats:bold>\n                    demonstrated two fold enhanced inhibitory potency and species\u2010specific disruption of M\u2010protein anchoring and biofilm formation in\n                    <jats:italic>Streptococcus pyogenes<\/jats:italic>\n                    , without affecting\n                    <jats:italic>Staphylococcus aureus<\/jats:italic>\n                    viability. In a\n                    <jats:italic>Galleria mellonella<\/jats:italic>\n                    infection model,\n                    <jats:bold>T10<\/jats:bold>\n                    conferred potent protection against lethal infection. This work demonstrates the development of narrow\u2010spectrum antivirulence agents through a structure\u2010based rational strategy.\n                  <\/jats:p>","DOI":"10.1002\/chem.202500464","type":"journal-article","created":{"date-parts":[[2025,3,12]],"date-time":"2025-03-12T09:38:31Z","timestamp":1741772311000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":2,"title":["Structure\u2010Based Development of a Covalent Inhibitor Targeting\n                    <i>Streptococcus Pyogenes<\/i>\n                    over\n                    <i>Staphylococcus Aureus<\/i>\n                    Sortase A"],"prefix":"10.1002","volume":"31","author":[{"given":"Hailing","family":"Zhou","sequence":"first","affiliation":[{"name":"State Key Laboratory of Drug Research, Centre for Chemical Biology Shanghai Institute of Materia Medica Chinese Academy of Sciences  Shanghai 201203 China"},{"name":"University of Chinese Academy of Sciences  Beijing 100049 China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ziqi","family":"Yuan","sequence":"additional","affiliation":[{"name":"State Key Laboratory of Drug Research, Centre for Chemical Biology Shanghai Institute of Materia Medica Chinese Academy of Sciences  Shanghai 201203 China"},{"name":"University of Chinese Academy of Sciences  Beijing 100049 China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xiang\u2010Na","family":"Guan","sequence":"additional","affiliation":[{"name":"State Key Laboratory of Drug Research, Centre for Chemical Biology Shanghai Institute of Materia Medica Chinese Academy of Sciences  Shanghai 201203 China"},{"name":"University of Chinese Academy of Sciences  Beijing 100049 China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Chuan","family":"Yue","sequence":"additional","affiliation":[{"name":"School of Chinese Materia Medica Nanjing University of Chinese Medicine  Nanjing 210023 China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Wei","family":"Wu","sequence":"additional","affiliation":[{"name":"State Key Laboratory of Drug Research, Centre for Chemical Biology Shanghai Institute of Materia Medica Chinese Academy of Sciences  Shanghai 201203 China"},{"name":"University of Chinese Academy of Sciences  Beijing 100049 China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lefu","family":"Lan","sequence":"additional","affiliation":[{"name":"School of Pharmaceutical Science and Technology Hangzhou Institute for Advanced Study University of Chinese Academy of Sciences  Hangzhou 310024 China"},{"name":"University of Chinese Academy of Sciences  Beijing 100049 China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jianhua","family":"Gan","sequence":"additional","affiliation":[{"name":"School of Life Sciences Fudan University  Shanghai 200433 China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3287-4629","authenticated-orcid":false,"given":"Tao","family":"Zhang","sequence":"additional","affiliation":[{"name":"State Key Laboratory of Drug Research, Centre for Chemical Biology Shanghai Institute of Materia Medica Chinese Academy of Sciences  Shanghai 201203 China"},{"name":"University of Chinese Academy of Sciences  Beijing 100049 China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5778-4422","authenticated-orcid":false,"given":"Cai\u2010Guang","family":"Yang","sequence":"additional","affiliation":[{"name":"State Key Laboratory of Drug Research, Centre for Chemical Biology Shanghai Institute of Materia Medica Chinese Academy of Sciences  Shanghai 201203 China"},{"name":"School of Chinese Materia Medica Nanjing University of Chinese Medicine  Nanjing 210023 China"},{"name":"School of Pharmaceutical Science and Technology Hangzhou Institute for Advanced Study University of Chinese Academy of Sciences  Hangzhou 310024 China"},{"name":"University of Chinese Academy of Sciences  Beijing 100049 China"},{"name":"Shandong Laboratory of Yantai Drug Discovery Bohai Rim Advanced Research Institute for Drug Discovery  Yantai 264117 China"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2025,3,24]]},"reference":[{"key":"e_1_2_8_1_1","doi-asserted-by":"publisher","DOI":"10.1128\/mr.59.2.171-200.1995"},{"key":"e_1_2_8_2_1","unstructured":"\u00a0"},{"key":"e_1_2_8_3_2","volume":"7","author":"Fischetti V. 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