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However, their clinical effectiveness is increasingly compromised by the widespread emergence of \u03b2\u2010lactamase\u2010mediated resistance. These enzymes hydrolyze the \u03b2\u2010lactam ring through an addition\u2013elimination mechanism, abolishing antibacterial activity. Preserving the efficacy of \u03b2\u2010lactam antibiotics, particularly carbapenems, regarded as the last line of defense against multidrug\u2010resistant (MDR) pathogens, is therefore critical. Here, we report the design and synthesis of compound\n                    <jats:bold>3<\/jats:bold>\n                    , a zwitterionic penicillin\u2010derived sulfone that integrates two key principles: enhanced permeability of zwitterionic molecules and improved inhibitory potency through (2\u2010pyridyl)methylene introduction within the sulbactam scaffold to achieve an adduct stable against hydrolysis. In vitro assays demonstrated that compound\n                    <jats:bold>3<\/jats:bold>\n                    significantly restored \u03b2\u2010lactam activity against MDR pathogens producing extended\u2010spectrum \u03b2\u2010lactamases (ESBLs) and carbapenem\u2010hydrolyzing class D \u03b2\u2010lactamases. It notably improved imipenem and ceftazidime efficacy against strains expressing OXA\u201048 and PDC\u20101, whose inhibitory capacity was determined by kinetic analysis with the isolated enzymes. Mechanistic studies using mass spectrometry and molecular dynamics simulations revealed ligand\u2010induced pocket formation, \u03c0\u2010stacking modulation, and hydrophobic engagement, supporting a covalent, water\u2010shielded inactivation pathway via indolizine adduct formation. The nonsterically hindered amine in\n                    <jats:bold>3<\/jats:bold>\n                    favored PDC\u20101 binding and overall permeability while exerting a neutral effect on OXA\u201048 binding. These results underscore the potential of compound\n                    <jats:bold>3<\/jats:bold>\n                    as a next\u2010generation \u03b2\u2010lactamase inhibitor for combating infections caused by ESBL\u2010 and carbapenemase\u2010producing Enterobacterales and\n                    <jats:italic>Pseudomonas aeruginosa<\/jats:italic>\n                    .\n                  <\/jats:p>","DOI":"10.1002\/cmdc.202600001","type":"journal-article","created":{"date-parts":[[2026,5,19]],"date-time":"2026-05-19T02:59:44Z","timestamp":1779159584000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Zwitterionic Penicillin\u2010Derived Sulfone Inhibitor for Combating \u03b2\u2010Lactamase\u2010Mediated Antibiotic Resistance"],"prefix":"10.1002","volume":"21","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-7868-8189","authenticated-orcid":false,"given":"Diana","family":"Rodr\u00edguez","sequence":"first","affiliation":[{"name":"Centro Singular de Investigaci\u00f3n en Qu\u00edmica Biol\u00f3xica e Materiais Moleculares (CIQUS) and Departamento de Qu\u00edmica Org\u00e1nica Universidade de Santiago de Compostela  Santiago de Compostela Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9489-9421","authenticated-orcid":false,"given":"Emilio","family":"Lence","sequence":"additional","affiliation":[{"name":"Centro Singular de Investigaci\u00f3n en Qu\u00edmica Biol\u00f3xica e Materiais Moleculares (CIQUS) and Departamento de Qu\u00edmica Org\u00e1nica Universidade de Santiago de Compostela  Santiago de Compostela Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4949-0779","authenticated-orcid":false,"given":"Juan C.","family":"V\u00e1zquez\u2010Ucha","sequence":"additional","affiliation":[{"name":"Servicio de Microbiolog\u00eda Complexo Hospitalario Universitario da Coru\u00f1a (CHUAC) Instituto de Investigaci\u00f3n Biom\u00e9dica da Coru\u00f1a (INIBIC)  A Coru\u00f1a Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6340-7815","authenticated-orcid":false,"given":"Alejandro","family":"Beceiro","sequence":"additional","affiliation":[{"name":"Servicio de Microbiolog\u00eda Complexo Hospitalario Universitario da Coru\u00f1a (CHUAC) Instituto de Investigaci\u00f3n Biom\u00e9dica da Coru\u00f1a (INIBIC)  A Coru\u00f1a Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6439-553X","authenticated-orcid":false,"given":"Concepci\u00f3n","family":"Gonz\u00e1lez\u2010Bello","sequence":"additional","affiliation":[{"name":"Centro Singular de Investigaci\u00f3n en Qu\u00edmica Biol\u00f3xica e Materiais Moleculares (CIQUS) and Departamento de Qu\u00edmica Org\u00e1nica Universidade de Santiago de Compostela  Santiago de Compostela Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2026,5,18]]},"reference":[{"key":"e_1_2_9_2_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.ejmech.2020.112829"},{"key":"e_1_2_9_3_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41586-024-07530-w"},{"key":"e_1_2_9_4_1","doi-asserted-by":"publisher","DOI":"10.1128\/AAC.00296-11"},{"key":"e_1_2_9_5_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41579-019-0159-8"},{"key":"e_1_2_9_6_1","doi-asserted-by":"publisher","DOI":"10.1093\/jacamr\/dlab092"},{"key":"e_1_2_9_7_1","doi-asserted-by":"publisher","DOI":"10.1021\/acs.jmedchem.9b01279"},{"key":"e_1_2_9_8_1","unstructured":"Beta\u2010Lactamase DataBase \u201cStructure and Function (BLDB) \u201d accessed January 5 2025 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