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Here, we reveal the intrinsic conformational architecture of 7-aminodesacetoxycephalosporanic acid (7-ADCA), the foundational core of cephalosporins, using laser ablation broadband rotational spectroscopy and high-level quantum chemical calculations. In a striking departure from the hydrogen-bond-mediated activation observed in penicillins, we discovered that 7-ADCA can be electronically preactivated by a subtle n \u2192 \u03c0* orbital interaction between the carboxylic oxygen and the \u03b2-lactam carbonyl. This interaction selectively weakens the amide bond without compromising the scaffold\u2019s overall stability, offering an evolutionary trade-off superior to the fragile penicillin nucleus. A comprehensive survey of the Protein Data Bank (PDB) confirms that this gas-phase geometry not only is the biologically operative pharmacophore but also is adopted by approximately 70% of enzyme-bound cephalosporins. These findings provide insights into the electronic features of the cephalosporin core and offer a structural template consistent with its bioactivity, potentially aiding in the rational design of next-generation antibiotics through subangstrom orbital tuning.<\/jats:p>","DOI":"10.1021\/acs.jpclett.6c01886","type":"journal-article","created":{"date-parts":[[2026,8,17]],"date-time":"2026-08-17T10:01:45Z","timestamp":1786960905000},"page":"9919-9926","source":"Crossref","is-referenced-by-count":0,"title":["Orbital Tuning\nof the \u03b2-Lactam Warhead:\nIntrinsic n \u2192 \u03c0* Preactivation in Cephalosporins"],"prefix":"10.1021","volume":"17","author":[{"given":"Sergio","family":"Mato","sequence":"first","affiliation":[{"name":"Universidad de Valladolid , , ,","place":["Valladolid, Spain, 47011"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sofi\u0301a","family":"Municio","sequence":"additional","affiliation":[{"name":"Universidad de Valladolid , , ,","place":["Valladolid, Spain, 47011"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jose\u0301 L.","family":"Alonso","sequence":"additional","affiliation":[{"name":"Universidad de Valladolid , , ,","place":["Valladolid, Spain, 47011"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5816-4102","authenticated-orcid":true,"given":"Elena R.","family":"Alonso","sequence":"additional","affiliation":[{"name":"Universidad de Valladolid , , ,","place":["Valladolid, Spain, 47011"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1992-935X","authenticated-orcid":true,"given":"Iker","family":"Leo\u0301n","sequence":"additional","affiliation":[{"name":"Universidad de Valladolid , , ,","place":["Valladolid, Spain, 47011"]}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"316","published-online":{"date-parts":[[2026,8,17]]},"reference":[{"issue":"8","key":"2026090114434087400_cit1","doi-asserted-by":"publisher","DOI":"10.1101\/cshperspect.a025247","article-title":"\u03b2-Lactams and \u03b2-Lactamase Inhibitors: An\nOverview","volume":"6","author":"Bush","year":"2016","journal-title":"Cold Spring Harb. 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Chem."},{"issue":"10325","key":"2026090114434087400_cit3","doi-asserted-by":"publisher","first-page":"629","DOI":"10.1016\/S0140-6736(21)02724-0","article-title":"Global Burden of Bacterial\nAntimicrobial Resistance in 2019: A Systematic Analysis","volume":"399","author":"Murray","year":"2022","journal-title":"Lancet"},{"key":"2026090114434087400_cit4","doi-asserted-by":"publisher","DOI":"10.1038\/d41586-022-00228-x","article-title":"The Staggering\nDeath Toll of Drug-Resistant Bacteria","author":"Thompson","year":"2022","journal-title":"Nature"},{"issue":"3","key":"2026090114434087400_cit5","doi-asserted-by":"publisher","first-page":"482","DOI":"10.3934\/microbiol.2018.3.482","article-title":"An Overview\nof the Antimicrobial Resistance Mechanisms of Bacteria","volume":"4","author":"Reygaert","year":"2018","journal-title":"AIMS Microbiol."},{"issue":"1","key":"2026090114434087400_cit6","doi-asserted-by":"publisher","first-page":"1","DOI":"10.1086\/595011","article-title":"Bad Bugs, No Drugs: No ESKAPE! 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