{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,26]],"date-time":"2026-09-26T03:43:05Z","timestamp":1790394185364,"version":"4.1.0"},"reference-count":52,"publisher":"American Society for Microbiology","issue":"10","license":[{"start":{"date-parts":[[2023,10,18]],"date-time":"2023-10-18T00:00:00Z","timestamp":1697587200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/doi.org\/10.1128\/ASMCopyrightv2"},{"start":{"date-parts":[[2023,10,18]],"date-time":"2023-10-18T00:00:00Z","timestamp":1697587200000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/journals.asm.org\/non-commercial-tdm-license"}],"funder":[{"name":"Merck","award":["MISP 57394"],"award-info":[{"award-number":["MISP 57394"]}]},{"DOI":"10.13039\/100000738","name":"U.S. Department of Veterans Affairs","doi-asserted-by":"crossref","award":["1I01BX001974"],"award-info":[{"award-number":["1I01BX001974"]}],"id":[{"id":"10.13039\/100000738","id-type":"DOI","asserted-by":"crossref"}]}],"content-domain":{"domain":["journals.asm.org"],"crossmark-restriction":true},"short-container-title":["Antimicrob Agents Chemother"],"published-print":{"date-parts":[[2023,10,18]]},"abstract":"<jats:title>ABSTRACT<\/jats:title>\n          <jats:p>\n            <jats:italic>Klebsiella pneumoniae<\/jats:italic>\n            carbapenemase-2 (KPC-2) presents a clinical threat as this \u03b2-lactamase confers resistance to carbapenems. Recent variants of KPC-2 in clinical isolates contribute to concerning resistance phenotypes.\n            <jats:italic>Klebsiella pneumoniae<\/jats:italic>\n            expressing KPC-2 D179Y acquired resistance to the ceftazidime\/avibactam combination affecting both the \u03b2-lactam and the \u03b2-lactamase inhibitor yet has lowered minimum inhibitory concentrations for all other \u03b2-lactams tested. Furthermore,\n            <jats:italic>Klebsiella pneumoniae<\/jats:italic>\n            expressing the KPC-2 D179N variant also manifested resistance to ceftazidime\/avibactam yet retained its ability to confer resistance to carbapenems although significantly reduced. This structural study focuses on the inhibition of KPC-2 D179N by avibactam and relebactam and expands our previous analysis that examined ceftazidime resistance conferred by D179N and D179Y variants. Crystal structures of KPC-2 D179N soaked with avibactam and co-crystallized with relebactam were determined. The complex with avibactam reveals avibactam making several hydrogen bonds, including with the deacylation water held in place by \u03a9 loop. These results could explain why the KPC-2 D179Y variant, which has a disordered \u03a9 loop, has a decreased affinity for avibactam. The relebactam KPC-2 D179N complex revealed a new orientation of the diazabicyclooctane (DBO) intermediate with the scaffold piperidine ring rotated ~150\u00b0 from the standard DBO orientation. The density shows relebactam to be desulfated and present as an imine-hydrolysis intermediate not previously observed. The tetrahedral imine moiety of relebactam interacts with the deacylation water. The rotated relebactam orientation and deacylation water interaction could potentially contribute to KPC-mediated DBO fragmentation. These results elucidate important differences that could aid in the design of novel \u03b2-lactamase inhibitors.\n          <\/jats:p>","DOI":"10.1128\/aac.00350-23","type":"journal-article","created":{"date-parts":[[2023,9,26]],"date-time":"2023-09-26T13:07:49Z","timestamp":1695733669000},"update-policy":"https:\/\/doi.org\/10.1128\/asmj-crossmark-policy-page","source":"Crossref","is-referenced-by-count":14,"title":["Exploring avibactam and relebactam inhibition of\n            <i>Klebsiella pneumoniae<\/i>\n            carbapenemase D179N variant: role of the \u03a9 loop-held deacylation water"],"prefix":"10.1128","volume":"67","author":[{"given":"T. A.","family":"Alsenani","sequence":"first","affiliation":[{"name":"Department of Biochemistry, Case Western Reserve University School of Medicine , Cleveland, Ohio, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"S. L.","family":"Viviani","sequence":"additional","affiliation":[{"name":"Department of Biochemistry, Case Western Reserve University School of Medicine , Cleveland, Ohio, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9976-7898","authenticated-orcid":false,"given":"K. M.","family":"Papp-Wallace","sequence":"additional","affiliation":[{"name":"Clinical Scientist Investigator, Louis Stokes Cleveland Department of Veterans Affairs Medical Center , North liberty, Iowa, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3299-894X","authenticated-orcid":false,"given":"R. A.","family":"Bonomo","sequence":"additional","affiliation":[{"name":"Department of Biochemistry, Case Western Reserve University School of Medicine , Cleveland, Ohio, USA"},{"name":"Clinical Scientist Investigator, Louis Stokes Cleveland Department of Veterans Affairs Medical Center , North liberty, Iowa, USA"},{"name":"Department of Medicine, Case Western Reserve University School of Medicine , Cleveland, Ohio, USA"},{"name":"Department of Molecular Biology and Microbiology, Case Western Reserve University School of Medicine , Cleveland, Ohio, USA"},{"name":"Department of Pharmacology, Case Western Reserve University School of Medicine , Cleveland, Ohio, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9210-3565","authenticated-orcid":false,"given":"F.","family":"van den Akker","sequence":"additional","affiliation":[{"name":"Department of Biochemistry, Case Western Reserve University School of Medicine , Cleveland, Ohio, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"235","reference":[{"key":"e_1_3_2_2_2","doi-asserted-by":"publisher","DOI":"10.1038\/s41579-019-0159-8"},{"key":"e_1_3_2_3_2","doi-asserted-by":"publisher","DOI":"10.1093\/glycob\/11.3.25r"},{"key":"e_1_3_2_4_2","doi-asserted-by":"publisher","DOI":"10.1093\/cid\/cix893"},{"key":"e_1_3_2_5_2","doi-asserted-by":"publisher","DOI":"10.1093\/jtm\/taw102"},{"key":"e_1_3_2_6_2","doi-asserted-by":"publisher","DOI":"10.1128\/AAC.01612-17"},{"key":"e_1_3_2_7_2","doi-asserted-by":"publisher","DOI":"10.1111\/1469-0691.12719"},{"key":"e_1_3_2_8_2","doi-asserted-by":"publisher","DOI":"10.1128\/AAC.04406-14"},{"key":"e_1_3_2_9_2","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.1205073109"},{"key":"e_1_3_2_10_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.bmcl.2013.12.101"},{"key":"e_1_3_2_11_2","doi-asserted-by":"publisher","DOI":"10.1128\/AAC.00174-18"},{"key":"e_1_3_2_12_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.clinthera.2020.01.023"},{"key":"e_1_3_2_13_2","doi-asserted-by":"publisher","DOI":"10.3390\/molecules27123832"},{"key":"e_1_3_2_14_2","first-page":"425","article-title":"Comparative in vitro activity of beta-lactam\/beta-lactamase inhibitor combinations against gram negative bacteria","volume":"122","author":"Mohanty S","year":"2005","unstructured":"Mohanty S , Singhal R , Sood S , Dhawan B , Das BK , Kapil A . 2005. 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