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In particular, it is unclear whether discrete substructures contribute independently to antibacterial activity or whether biological function depends on the integrity of the full molecular framework. Here, we report the synthesis and biological evaluation of a series of structurally defined fragments derived from vancoresmycin and its aglycon amycomycin, including the tetramic acid core, eastern and western polyketide segments, and the mycosamine residue. Despite preserving key structural motifs, the fragments did not exhibit considerable antibacterial activity. Only the western fragment displayed weak activity accompanied by indications of membrane\u2010associated stress. These results demonstrate that antibacterial activity in vancoresmycin cannot be attributed to isolated substructures but instead depends on the integrated molecular architecture. These results provide a framework for future design strategies that preserve global structural properties rather than focusing on discrete motifs.<\/jats:p>","DOI":"10.1002\/cmdc.70409","type":"journal-article","created":{"date-parts":[[2026,7,31]],"date-time":"2026-07-31T00:36:35Z","timestamp":1785458195000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":1,"title":["Fragmentation of Vancoresmycin Reveals a Strong Dependence on Global Molecular Architecture for Antibacterial Activity"],"prefix":"10.1002","volume":"21","author":[{"ORCID":"https:\/\/orcid.org\/0009-0005-3277-0805","authenticated-orcid":false,"given":"Max","family":"Sch\u00f6nenbroicher","sequence":"first","affiliation":[{"name":"Kekul\u00e9\u2010Institute for Organic Chemistry and Biochemistry University of Bonn  Bonn Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0003-2930-5019","authenticated-orcid":false,"given":"Florian","family":"Heppner","sequence":"additional","affiliation":[{"name":"Kekul\u00e9\u2010Institute for Organic Chemistry and Biochemistry University of Bonn  Bonn Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Maximilian","family":"Seul","sequence":"additional","affiliation":[{"name":"Kekul\u00e9\u2010Institute for Organic Chemistry and Biochemistry University of Bonn  Bonn Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Simon","family":"Morgenschweis","sequence":"additional","affiliation":[{"name":"Kekul\u00e9\u2010Institute for Organic Chemistry and Biochemistry University of Bonn  Bonn Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Aia Ali","family":"Abdelrahman","sequence":"additional","affiliation":[{"name":"Institute of Pharmaceutical Microbiology University Hospital Bonn University of Bonn  Bonn Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Eva","family":"Fahr","sequence":"additional","affiliation":[{"name":"Institute of Pharmaceutical Microbiology University Hospital Bonn University of Bonn  Bonn Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0004-3134-9341","authenticated-orcid":false,"given":"Niklas","family":"Holstein","sequence":"additional","affiliation":[{"name":"Institute of Pharmaceutical Microbiology University Hospital Bonn University of Bonn  Bonn Germany"},{"name":"German Center for Infection Research (DZIF), Partner Site Bonn\u2010Cologne  Bonn Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6420-3868","authenticated-orcid":false,"given":"Anna","family":"M\u00fcller","sequence":"additional","affiliation":[{"name":"Institute of Pharmaceutical Microbiology University Hospital Bonn University of Bonn  Bonn Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4724-8383","authenticated-orcid":false,"given":"Dirk","family":"Menche","sequence":"additional","affiliation":[{"name":"Kekul\u00e9\u2010Institute for Organic Chemistry and Biochemistry University of Bonn  Bonn Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2026,7,30]]},"reference":[{"key":"e_1_2_8_2_1","doi-asserted-by":"publisher","DOI":"10.1007\/s00253-003-1536-8"},{"key":"e_1_2_8_3_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.bmc.2008.02.069"},{"key":"e_1_2_8_4_1","doi-asserted-by":"publisher","DOI":"10.1021\/cr00038a009"},{"key":"e_1_2_8_5_1","doi-asserted-by":"publisher","DOI":"10.1016\/S0040-4039(01)02171-2"},{"key":"e_1_2_8_6_1","unstructured":"C.Hopmann M.Kurz H.Decker D. 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