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Calcium\u2010dependent antibiotics (CDAs) are promising candidates to combat infectious diseases as many of them show modes of action (MOA) orthogonal to widespread resistance mechanisms. The calcium dependence is nonetheless one of the hurdles toward realizing their full potential. Using laspartomycin C (LspC) as a model, we explored the possibility of reducing, or even eliminating, its calcium dependence. We report herein a synthetic LspC analogue (<jats:bold>B1<\/jats:bold>) whose activity no longer depends on calcium and is instead induced by phenylboronic acid (PBA). In LspC, Asp1 and Asp7 coordinate to calcium to anchor it in the active conformation; these residues are replaced by serine in <jats:bold>B1<\/jats:bold> and condense with PBA to form a boronic ester with the same anchoring effect. Using thin\u2010layer chromatography, MS, NMR, and complementation assays, we demonstrate that <jats:bold>B1<\/jats:bold> inhibits bacterial growth via the same MOA as LspC, i.e., sequestering the cell wall biosynthetic intermediate undecaprenyl phosphate. <jats:bold>B1<\/jats:bold> is as potent and effective as LspC against several Gram\u2010positive bacteria, including methicillin\u2010resistant <jats:italic>Staphylococcus aureus<\/jats:italic> and vancomycin\u2010resistant <jats:italic>Enterococcus<\/jats:italic>. Our success in converting a CDA to a boron\u2010dependent antibiotic opens a new avenue in the design and functional control of drug molecules.<\/jats:p>","DOI":"10.1002\/anie.202317522","type":"journal-article","created":{"date-parts":[[2023,12,13]],"date-time":"2023-12-13T01:19:37Z","timestamp":1702430377000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":3,"title":["A Boron\u2010Dependent Antibiotic Derived from a Calcium\u2010Dependent Antibiotic"],"prefix":"10.1002","volume":"63","author":[{"ORCID":"https:\/\/orcid.org\/0009-0003-5502-4966","authenticated-orcid":false,"given":"Shao\u2010Lun","family":"Chiou","sequence":"first","affiliation":[{"name":"Department of Chemistry National Taiwan University  No. 1, Sec. 4, Roosevelt Rd. 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