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Their antibacterial activity stems from an unprecedented dual mechanism: the lower binding sites occupy the adenosine triphosphate (ATP) binding pocket of bacterial type II topoisomerases, while the upper binding sites disrupt the enzyme dimer interface. This dual action, combined with their unique chemical structures, positions KBD and AMM as promising scaffolds for developing new antibiotics. However, the structure\u2013activity relationship (SAR) of KBD\/AMM remains underexplored due to their highly complex chemical structures. In this study, we utilized total synthesis to produce KBD\/AMM analogs with various site modifications and evaluated their antimicrobial activities. Our findings establish the first comprehensive SAR for KBD\/AMM, paving the way for the development of novel KBD\/AMM\u2010based antibiotics.\n                  <\/jats:p>","DOI":"10.1002\/anie.202415439","type":"journal-article","created":{"date-parts":[[2024,9,30]],"date-time":"2024-09-30T04:31:11Z","timestamp":1727670671000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":6,"title":["Establishing the Comprehensive Structure\u2212Activity Relationship of the Natural Antibiotic Kibdelomycin\/Amycolamicin"],"prefix":"10.1002","volume":"64","author":[{"given":"Chenglong","family":"Chen","sequence":"first","affiliation":[{"name":"College of Life Sciences Beijing Normal University  No. 19, Xinjiekouwai St, Haidian District Beijing 100875 P.R. China"},{"name":"National Institute of Biological Sciences, Beijing  7 Science Park Road ZGC Life Science Park Beijing 102206 P.R. China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yuyao","family":"Yin","sequence":"additional","affiliation":[{"name":"Department of Clinical Laboratory Peking University People's Hospital  No.11 Xizhimen South Street, Xicheng District Beijing P.R. China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Panrui","family":"Lu","sequence":"additional","affiliation":[{"name":"National Institute of Biological Sciences, Beijing  7 Science Park Road ZGC Life Science Park Beijing 102206 P.R. China"},{"name":"Tsinghua Institute of Multidisciplinary Biomedical Research Tsinghua University, Beijing  7 Science Park Road ZGC Life Science Park Beijing 102206 P.R. China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ting","family":"Han","sequence":"additional","affiliation":[{"name":"National Institute of Biological Sciences, Beijing  7 Science Park Road ZGC Life Science Park Beijing 102206 P.R. 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