{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,2]],"date-time":"2026-09-02T18:51:10Z","timestamp":1788375070105,"version":"build-2803163510"},"reference-count":58,"publisher":"MDPI AG","issue":"5","license":[{"start":{"date-parts":[[2023,5,11]],"date-time":"2023-05-11T00:00:00Z","timestamp":1683763200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"Merck, Sharp &amp; Dohme, Kenilworth, NJ USA","award":["MISP #57394"],"award-info":[{"award-number":["MISP #57394"]}]},{"name":"Merck, Sharp &amp; Dohme, Kenilworth, NJ USA","award":["1I01BX002872"],"award-info":[{"award-number":["1I01BX002872"]}]},{"name":"Merck, Sharp &amp; Dohme, Kenilworth, NJ USA","award":["1I01BX001974"],"award-info":[{"award-number":["1I01BX001974"]}]},{"name":"Merck, Sharp &amp; Dohme, Kenilworth, NJ USA","award":["VISN 10"],"award-info":[{"award-number":["VISN 10"]}]},{"name":"Cleveland Department of Veterans Affairs","award":["MISP #57394"],"award-info":[{"award-number":["MISP #57394"]}]},{"name":"Cleveland Department of Veterans Affairs","award":["1I01BX002872"],"award-info":[{"award-number":["1I01BX002872"]}]},{"name":"Cleveland Department of Veterans Affairs","award":["1I01BX001974"],"award-info":[{"award-number":["1I01BX001974"]}]},{"name":"Cleveland Department of Veterans Affairs","award":["VISN 10"],"award-info":[{"award-number":["VISN 10"]}]},{"DOI":"10.13039\/100000738","name":"Veterans Affairs Merit Review Program","doi-asserted-by":"publisher","award":["MISP #57394"],"award-info":[{"award-number":["MISP #57394"]}],"id":[{"id":"10.13039\/100000738","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000738","name":"Veterans Affairs Merit Review Program","doi-asserted-by":"publisher","award":["1I01BX002872"],"award-info":[{"award-number":["1I01BX002872"]}],"id":[{"id":"10.13039\/100000738","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000738","name":"Veterans Affairs Merit Review Program","doi-asserted-by":"publisher","award":["1I01BX001974"],"award-info":[{"award-number":["1I01BX001974"]}],"id":[{"id":"10.13039\/100000738","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000738","name":"Veterans Affairs Merit Review Program","doi-asserted-by":"publisher","award":["VISN 10"],"award-info":[{"award-number":["VISN 10"]}],"id":[{"id":"10.13039\/100000738","id-type":"DOI","asserted-by":"publisher"}]},{"name":"Biomedical Laboratory Research &amp; Development Service of the VA Office of Research and Development and the Geriatric Research Education and Clinical Center","award":["MISP #57394"],"award-info":[{"award-number":["MISP #57394"]}]},{"name":"Biomedical Laboratory Research &amp; Development Service of the VA Office of Research and Development and the Geriatric Research Education and Clinical Center","award":["1I01BX002872"],"award-info":[{"award-number":["1I01BX002872"]}]},{"name":"Biomedical Laboratory Research &amp; Development Service of the VA Office of Research and Development and the Geriatric Research Education and Clinical Center","award":["1I01BX001974"],"award-info":[{"award-number":["1I01BX001974"]}]},{"name":"Biomedical Laboratory Research &amp; Development Service of the VA Office of Research and Development and the Geriatric Research Education and Clinical Center","award":["VISN 10"],"award-info":[{"award-number":["VISN 10"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Antibiotics"],"abstract":"<jats:p>Background: Ceftazidime-avibactam was approved by the FDA to treat infections caused by Enterobacterales carrying blaKPC-2. However, variants of KPC-2 with amino acid substitutions at position 179 have emerged and confer resistance to ceftazidime-avibactam. Methods: The activity of imipenem-relebactam was assessed against a panel of 19 KPC-2 D179 variants. KPC-2 and the D179N and D179Y variants were purified for biochemical analyses. Molecular models were constructed with imipenem to assess differences in kinetic profiles. Results: All strains were susceptible to imipenem\u2013relebactam, but resistant to ceftazidime (19\/19) and ceftazidime-avibactam (18\/19). KPC-2 and the D179N variant hydrolyzed imipenem, but the D179N variant\u2019s rate was much slower. The D179Y variant was unable to turnover imipenem. All three \u03b2-lactamases hydrolyzed ceftazidime at varying rates. The acylation rate of relebactam for the D179N variant was ~2.5\u00d7 lower than KPC-2. Poor catalytic turnover by the D179Y variant precluded the determination of inhibitory kinetic parameters. Acyl-complexes with imipenem and ceftazidime were less prevalent with the D179N variant compared to the D179Y variant, supporting the kinetic observations that the D179Y variant was not as active as the D179N variant. Relebactam was slower to form an acyl-complex with the D179Y variant compared to avibactam. The D179Y model with imipenem revealed that the catalytic water molecule was shifted, and the carbonyl of imipenem was not within the oxyanion hole. Conversely in the D179N model, imipenem was oriented favorably for deacylation. Conclusions: Imipenem\u2013relebactam overcame the resistance of the D179 variants, suggesting that this combination will be active against clinical isolates harboring these derivatives of KPC-2.<\/jats:p>","DOI":"10.3390\/antibiotics12050892","type":"journal-article","created":{"date-parts":[[2023,5,11]],"date-time":"2023-05-11T04:29:01Z","timestamp":1683779341000},"page":"892","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":10,"title":["The Effectiveness of Imipenem\u2013Relebactam against Ceftazidime-Avibactam Resistant Variants of the KPC-2 \u03b2-Lactamase"],"prefix":"10.3390","volume":"12","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-9976-7898","authenticated-orcid":false,"given":"Krisztina M.","family":"Papp-Wallace","sequence":"first","affiliation":[{"name":"Research Service, Veterans Affairs Northeast Ohio Healthcare System, Cleveland, OH 44106, USA"},{"name":"Department of Medicine, Case Western Reserve University, Cleveland, OH 44106, USA"},{"name":"Department of Biochemistry, Case Western Reserve University, Cleveland, OH 44106, USA"},{"name":"JMI Laboratories, a Subsidiary of Element Materials Technology, North Liberty, IA 52317, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Melissa D.","family":"Barnes","sequence":"additional","affiliation":[{"name":"Research Service, Veterans Affairs Northeast Ohio Healthcare System, Cleveland, OH 44106, USA"},{"name":"Department of Medicine, Case Western Reserve University, Cleveland, OH 44106, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Magdalena A.","family":"Taracila","sequence":"additional","affiliation":[{"name":"Research Service, Veterans Affairs Northeast Ohio Healthcare System, Cleveland, OH 44106, USA"},{"name":"Department of Medicine, Case Western Reserve University, Cleveland, OH 44106, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Christopher R.","family":"Bethel","sequence":"additional","affiliation":[{"name":"Research Service, Veterans Affairs Northeast Ohio Healthcare System, Cleveland, OH 44106, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Joseph D.","family":"Rutter","sequence":"additional","affiliation":[{"name":"Research Service, Veterans Affairs Northeast Ohio Healthcare System, Cleveland, OH 44106, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Elise T.","family":"Zeiser","sequence":"additional","affiliation":[{"name":"Research Service, Veterans Affairs Northeast Ohio Healthcare System, Cleveland, OH 44106, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Katherine","family":"Young","sequence":"additional","affiliation":[{"name":"Merck & Co., Inc., Kenilworth, NJ 07033, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Robert A.","family":"Bonomo","sequence":"additional","affiliation":[{"name":"Research Service, Veterans Affairs Northeast Ohio Healthcare System, Cleveland, OH 44106, USA"},{"name":"Department of Medicine, Case Western Reserve University, Cleveland, OH 44106, USA"},{"name":"Department of Biochemistry, Case Western Reserve University, Cleveland, OH 44106, USA"},{"name":"GRECC, Veterans Affairs Northeast Ohio Healthcare System, Cleveland, OH 44106, USA"},{"name":"Departments of Pharmacology, Molecular Biology and Microbiology, Proteomics and Bioinformatics, School of Medicine, Case Western Reserve University, Cleveland, OH 44106, USA"},{"name":"CWRU-Cleveland VAMC Center for Antimicrobial Resistance and Epidemiology (Case VA CARES), Cleveland, OH 44106, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2023,5,11]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"113","DOI":"10.1007\/s10928-017-9506-4","article-title":"What we may expect from novel antibacterial agents in the pipeline with respect to resistance and pharmacodynamic principles","volume":"44","author":"Bush","year":"2017","journal-title":"J. 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