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The rational design of compounds to expand their antibacterial spectra of antibiotics solely targeting Gram\u2010positive pathogens remains challenging. Here, the design of skeletons from natural products to penetrate the OM are deciphered. Structure\u2010activity relationship analysis shows the optimization of the model of natural xanthones \u03b1\u2010mangostin endows the broad\u2010spectrum antibacterial activity. Mechanistic studies demonstrate the lead compound A20 penetrates the OM in a self\u2010promoted pathway through electronic and hydrophobic interactions with lipopolysaccharides and phospholipids in OM. A20 displays rapid bactericidal activity by targeting the cofactor heme in the respiratory complex. The therapeutic efficacy of A20 is demonstrated in two animal models infected with multidrug\u2010resistant Gram\u2010negative bacterial pathogens. The findings elucidate the structural property and self\u2010promoted transportation of a class of antibacterial compounds, to facilitate the design and discovery of antibacterial agents against increasingly prevalent Gram\u2010negative pathogens associated with infections.<\/jats:p>","DOI":"10.1002\/advs.202411923","type":"journal-article","created":{"date-parts":[[2025,1,30]],"date-time":"2025-01-30T10:45:17Z","timestamp":1738233917000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":15,"title":["Rational Design of Natural Xanthones Against Gram\u2010negative Bacteria"],"prefix":"10.1002","volume":"12","author":[{"given":"Xiaojia","family":"Liu","sequence":"first","affiliation":[{"name":"National Key Laboratory of Veterinary Public Health and Safety College of Veterinary Medicine China Agricultural University  No.2 Yuanmingyuan West Road Beijing 100193 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