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Resistance in CRE is often associated with production of K. pneumoniae (KPC) carbapenemases. We report a structurally modified meropenem derivative, JDB-1-200 (i.e., 8-epi-meropenem, in which the stereochemistry of the C8 hydroxyl is inverted), displaying enhanced activity relative to meropenem against KPC-producing CRE. JDB-1-200 alone displayed superior activity (MICs of 0.5 to 1 mg\/L, compared with &amp;gt;8 mg\/L for meropenem) against several clinically relevant Enterobacterales, including KPC-producing K. pneumoniae and Citrobacter freundii. Crystallographic analysis of JDB-1-200 complexes with the E166Q deacylation-deficient KPC-2 mutant, compared with an analogous meropenem (8R-hydroxyl) complex, indicates that the improvement arises from the JDB 8S-hydroxyl group acting as a hydrogen-bond donor to the hydrolytic water, slowing acyl-enzyme hydrolysis, with similar interactions observed in a CTX-M-15:JDB-1-200 complex. Kinetic inhibition data for KPC-2 and CTX-M-15 indicate that JDB-1-200 could be used alone or alongside a \u03b2-lactamase inhibitor for effective CRE treatment.<\/jats:p>","DOI":"10.1021\/acsinfecdis.6c00607","type":"journal-article","created":{"date-parts":[[2026,9,8]],"date-time":"2026-09-08T11:02:14Z","timestamp":1788865334000},"page":"3514-3529","source":"Crossref","is-referenced-by-count":0,"title":["JDB-1-200, an\nAtypically Modified Carbapenem with\nStandalone\n                    <i>In Vitro<\/i>\n                    Activity against KPC-Producing\nEnterobacterales"],"prefix":"10.1021","volume":"12","author":[{"given":"Taariq","family":"Hassan","sequence":"first","affiliation":[{"name":"Southern Methodist University , , , ,","place":["Dallas, Texas, United States, 75275"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Svanik","family":"Jaikumar","sequence":"additional","affiliation":[{"name":"Southern Methodist University , , , ,","place":["Dallas, Texas, United States, 75275"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Diya","family":"Patel","sequence":"additional","affiliation":[{"name":"Southern Methodist University , , , ,","place":["Dallas, Texas, United States, 75275"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Pojun","family":"Quan","sequence":"additional","affiliation":[{"name":"Southern Methodist University , , , ,","place":["Dallas, Texas, United States, 75275"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Maidileyvis Castro","family":"Cabello","sequence":"additional","affiliation":[{"name":"Southern Methodist University , , , ,","place":["Dallas, Texas, United States, 75275"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0009-8033-3828","authenticated-orcid":true,"given":"Jonathan E.","family":"Cox","sequence":"additional","affiliation":[{"name":"Southern Methodist University , , , ,","place":["Dallas, Texas, United States, 75275"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Md Mahbub Kabir","family":"Khan","sequence":"additional","affiliation":[{"name":"Southern Methodist University , , , ,","place":["Dallas, Texas, United States, 75275"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4602-0571","authenticated-orcid":true,"given":"James","family":"Spencer","sequence":"additional","affiliation":[{"name":"University of Bristol , , Biomedical Sciences Building, University Walk , ,","place":["Bristol, U.K., BS8 1TD"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Catherine L.","family":"Tooke","sequence":"additional","affiliation":[{"name":"University of Bath , , Claverton Down , ,","place":["Bath, U.K., BA2 7AY"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1007-791X","authenticated-orcid":true,"given":"John D.","family":"Buynak","sequence":"additional","affiliation":[{"name":"Southern Methodist University , , , ,","place":["Dallas, Texas, United States, 75275"]}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"316","published-online":{"date-parts":[[2026,9,8]]},"reference":[{"issue":"3","key":"2026100909103721900_cit1","doi-asserted-by":"publisher","first-page":"122","DOI":"10.3390\/antibiotics8030122","article-title":"Present and Future of Carbapenem-resistant\nEnterobacteriaceae (CRE) Infections","volume":"8","author":"Suay-Garci\u0301a","year":"2019","journal-title":"Antibiotics"},{"issue":"6","key":"2026100909103721900_cit2","doi-asserted-by":"publisher","first-page":"587","DOI":"10.3390\/antibiotics14060587","article-title":"Challenges of Carbapenem-Resistant\nEnterobacteriaceae in the Development of New \u03b2-Lactamase Inhibitors\nand Antibiotics","volume":"14","author":"Leroux","year":"2025","journal-title":"Antibiotics"},{"issue":"1","key":"2026100909103721900_cit3","doi-asserted-by":"publisher","first-page":"37","DOI":"10.3390\/antibiotics15010037","article-title":"Antibiotic\nResistance in Klebsiella pneumoniae and Related Enterobacterales:\nMolecular Mechanisms, Mobile Elements, and Therapeutic Challenges","volume":"15","author":"Zdarska","year":"2026","journal-title":"Antibiotics"},{"issue":"1","key":"2026100909103721900_cit4","doi-asserted-by":"publisher","first-page":"69","DOI":"10.1186\/s12879-023-08018-0","article-title":"The factors\nassociated with the trend\nin incidence of Bacteraemia and associated mortality over 30 years","volume":"23","author":"Garci\u0301a-Rodri\u0301guez","year":"2023","journal-title":"BMC Infect Dis."},{"issue":"7","key":"2026100909103721900_cit5","doi-asserted-by":"publisher","DOI":"10.1128\/AAC.00355-19","article-title":"The Microbiology\nof Bloodstream Infection:\n20-Year Trends from the SENTRY Antimicrobial Surveillance Program","volume":"63","author":"Diekema","year":"2019","journal-title":"Antimicrob. 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