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Here, we chemically engineer a class of anionic adjuvants to tailor their interactions with MBL, enhancing the enzymatic inhibition by up to ~5885-fold compared to parent compounds. An orthogonal screen identifies the tiopronin-engineered anionic adjuvant (TINA), which achieves complete rescue of all tested carbapenems against diverse New Delhi metallo-\u03b2-lactamase-1\u2013producing Gram-negative ESKAPE bacteria. TINA targets both MBL and LPS, depriving divalent cations to inactivate MBL and damage membrane collaboratively while also preventing resistance evolution. Moreover, TINA\u2019s anionic nature minimizes serum adsorption, enabling safe and effective in vivo treatment of bacterial pneumonia. This work provides an innovative chemical biology strategy leveraging anionic materials to combat superbugs globally.<\/jats:p>","DOI":"10.1126\/sciadv.adz0574","type":"journal-article","created":{"date-parts":[[2025,10,22]],"date-time":"2025-10-22T17:59:42Z","timestamp":1761155982000},"update-policy":"https:\/\/doi.org\/10.34133\/aaas_crossmark","source":"Crossref","is-referenced-by-count":9,"title":["Chemically tailored anionic antibiotic adjuvants targeting divalent cations to overcome carbapenem resistance in gram-negative bacteria"],"prefix":"10.1126","volume":"11","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-5009-6165","authenticated-orcid":true,"given":"Hao","family":"Tang","sequence":"first","affiliation":[{"name":"Guangdong Provincial Key Laboratory of Advanced Biomaterials, Department of Biomedical Engineering, Southern University of Science and Technology, Shenzhen, Guangdong 518055, P. R. 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