{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,26]],"date-time":"2026-09-26T03:43:04Z","timestamp":1790394184234,"version":"4.1.0"},"reference-count":44,"publisher":"American Society for Microbiology","issue":"3","license":[{"start":{"date-parts":[[2025,3,5]],"date-time":"2025-03-05T00:00:00Z","timestamp":1741132800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"},{"start":{"date-parts":[[2025,3,5]],"date-time":"2025-03-05T00:00:00Z","timestamp":1741132800000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/journals.asm.org\/non-commercial-tdm-license"}],"content-domain":{"domain":["journals.asm.org"],"crossmark-restriction":true},"short-container-title":["Antimicrob Agents Chemother"],"published-print":{"date-parts":[[2025,3,5]]},"abstract":"<jats:title>ABSTRACT<\/jats:title>\n                  <jats:sec>\n                    <jats:title\/>\n                    <jats:p>\n                      <jats:italic>Klebsiella pneumoniae<\/jats:italic>\n                      carbapenemases (KPCs) are widespread \u03b2-lactamases that are a major cause of clinical non-susceptibility of Gram-negative bacteria to carbapenems and other \u03b2-lactam antibiotics. Ceftazidime combined with the \u03b2-lactamase inhibitor avibactam (CAZ\u2013AVI) has been effective in treating infections by KPC-producing bacteria, but emerging KPC variants confer resistance to the combination. Taniborbactam and ledaborbactam are bicyclic boronate \u03b2-lactamase inhibitors currently under development with cefepime and ceftibuten, respectively, to treat carbapenem-resistant bacterial infections. Here, we assessed the effects of clinically important KPC-2 and KPC-3 variants (V240G, D179Y, and D179Y\/T243M) on the antibacterial activity of cefepime\u2013taniborbactam (FEP\u2013TAN) and ceftibuten\u2013ledaborbactam (CTB\u2013LED) and examined catalytic activity and inhibition of these variants. Unlike CAZ\u2013AVI, FEP\u2013TAN and CTB\u2013LED were highly active against\n                      <jats:italic>Escherichia coli<\/jats:italic>\n                      strains expressing these KPC variants. Experiments with purified enzymes showed that FEP and CTB were poorly hydrolyzed by the KPC variants and had weak affinity for variants containing D179Y. In addition, the D179Y substitution in KPC-2 reduced inhibition by TAN and LED, but inactivation efficiencies (\n                      <jats:italic>k<\/jats:italic>\n                      <jats:sub>2<\/jats:sub>\n                      \/\n                      <jats:italic>K<\/jats:italic>\n                      ) for these inhibitors were significantly higher than those for AVI.\n                      <jats:italic>K<\/jats:italic>\n                      <jats:sub>2<\/jats:sub>\n                      \/\n                      <jats:italic>K<\/jats:italic>\n                      was less affected for D179Y-containing KPC-3 variants, and robust inhibition was observed by TAN, LED, and AVI. Together, the findings illustrate a biochemical basis for FEP\u2013TAN and CTB\u2013LED efficacy in KPC variant-mediated CAZ\u2013AVI resistance backgrounds, whereby the boronate inhibitors have sufficient inhibitory activity, while FEP and CTB are poor substrates and bind to the variant enzymes with reduced affinity.\n                    <\/jats:p>\n                  <\/jats:sec>","DOI":"10.1128\/aac.01511-24","type":"journal-article","created":{"date-parts":[[2025,2,10]],"date-time":"2025-02-10T09:01:20Z","timestamp":1739178080000},"update-policy":"https:\/\/doi.org\/10.1128\/asmj-crossmark-policy-page","source":"Crossref","is-referenced-by-count":13,"title":["Cefepime\u2013taniborbactam and ceftibuten\u2013ledaborbactam maintain activity against KPC variants that lead to ceftazidime\u2013avibactam resistance"],"prefix":"10.1128","volume":"69","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-5789-2260","authenticated-orcid":true,"given":"Cullen L.","family":"Myers","sequence":"first","affiliation":[{"name":"Department of Molecular and Cellular Biology, University of Guelph","place":["Guelph, Canada"]},{"name":"Venatorx Pharmaceuticals Inc.","place":["Malvern, USA"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Annie","family":"Stevenson","sequence":"additional","affiliation":[{"name":"Venatorx Pharmaceuticals Inc.","place":["Malvern, USA"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Brittany","family":"Miller","sequence":"additional","affiliation":[{"name":"Venatorx Pharmaceuticals Inc.","place":["Malvern, USA"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9287-2997","authenticated-orcid":true,"given":"Denis M.","family":"Daigle","sequence":"additional","affiliation":[{"name":"Venatorx Pharmaceuticals Inc.","place":["Malvern, USA"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6994-4286","authenticated-orcid":true,"given":"Tsuyoshi","family":"Uehara","sequence":"additional","affiliation":[{"name":"Venatorx Pharmaceuticals Inc.","place":["Malvern, USA"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Daniel C.","family":"Pevear","sequence":"additional","affiliation":[{"name":"Venatorx Pharmaceuticals Inc.","place":["Malvern, USA"]}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"235","reference":[{"key":"e_1_3_2_2_2","doi-asserted-by":"publisher","DOI":"10.1128\/CMR.00047-19"},{"key":"e_1_3_2_3_2","doi-asserted-by":"publisher","DOI":"10.1128\/AAC.01009-09"},{"key":"e_1_3_2_4_2","doi-asserted-by":"publisher","DOI":"10.1080\/21505594.2016.1222343"},{"key":"e_1_3_2_5_2","doi-asserted-by":"publisher","DOI":"10.1093\/cid\/cix893"},{"key":"e_1_3_2_6_2","doi-asserted-by":"publisher","DOI":"10.1038\/s41579-019-0159-8"},{"key":"e_1_3_2_7_2","doi-asserted-by":"publisher","DOI":"10.1128\/AAC.02643-15"},{"key":"e_1_3_2_8_2","doi-asserted-by":"publisher","DOI":"10.1128\/AAC.00693-09"},{"key":"e_1_3_2_9_2","doi-asserted-by":"publisher","DOI":"10.1021\/acs.jmedchem.9b01279"},{"key":"e_1_3_2_10_2","doi-asserted-by":"publisher","DOI":"10.1021\/acs.jmedchem.9b01976"},{"key":"e_1_3_2_11_2","doi-asserted-by":"publisher","DOI":"10.1093\/cid\/ciw639"},{"key":"e_1_3_2_12_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.idc.2016.02.007"},{"key":"e_1_3_2_13_2","doi-asserted-by":"publisher","DOI":"10.1002\/phar.2092"},{"key":"e_1_3_2_14_2","doi-asserted-by":"publisher","DOI":"10.1128\/AAC.00678-15"},{"key":"e_1_3_2_15_2","doi-asserted-by":"publisher","DOI":"10.1128\/AAC.00079-17"},{"key":"e_1_3_2_16_2","doi-asserted-by":"publisher","DOI":"10.1093\/jac\/dkz026"},{"key":"e_1_3_2_17_2","doi-asserted-by":"publisher","DOI":"10.1093\/jac\/dkz201"},{"key":"e_1_3_2_18_2","doi-asserted-by":"publisher","DOI":"10.1128\/aac.02414-21"},{"key":"e_1_3_2_19_2","doi-asserted-by":"publisher","DOI":"10.1128\/AAC.02101-17"},{"key":"e_1_3_2_20_2","doi-asserted-by":"publisher","DOI":"10.1128\/AAC.02097-16"},{"key":"e_1_3_2_21_2","doi-asserted-by":"publisher","DOI":"10.1128\/AAC.00451-17"},{"key":"e_1_3_2_22_2","doi-asserted-by":"publisher","DOI":"10.1128\/mBio.00528-17"},{"key":"e_1_3_2_23_2","doi-asserted-by":"publisher","DOI":"10.1128\/AAC.01936-19"},{"key":"e_1_3_2_24_2","doi-asserted-by":"publisher","DOI":"10.1021\/acs.jmedchem.9b01518"},{"key":"e_1_3_2_25_2","doi-asserted-by":"publisher","DOI":"10.1128\/AAC.01963-19"},{"key":"e_1_3_2_26_2","doi-asserted-by":"publisher","DOI":"10.1056\/NEJMoa2304748"},{"key":"e_1_3_2_27_2","doi-asserted-by":"publisher","DOI":"10.1021\/acs.jmedchem.1c00437"},{"key":"e_1_3_2_28_2","doi-asserted-by":"publisher","DOI":"10.1128\/AAC.00552-21"},{"key":"e_1_3_2_29_2","doi-asserted-by":"publisher","DOI":"10.1128\/AAC.45.6.1868-1871.2001"},{"key":"e_1_3_2_30_2","doi-asserted-by":"publisher","DOI":"10.1371\/journal.ppat.1004949"},{"key":"e_1_3_2_31_2","doi-asserted-by":"publisher","DOI":"10.1021\/acsinfecdis.0c00575"},{"key":"e_1_3_2_32_2","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pone.0136813"},{"key":"e_1_3_2_33_2","doi-asserted-by":"publisher","DOI":"10.1039\/c9md00557a"},{"key":"e_1_3_2_34_2","doi-asserted-by":"publisher","DOI":"10.1002\/pro.454"},{"key":"e_1_3_2_35_2","doi-asserted-by":"publisher","DOI":"10.1128\/aac.02124-21"},{"key":"e_1_3_2_36_2","doi-asserted-by":"publisher","DOI":"10.1128\/aac.00447-22"},{"key":"e_1_3_2_37_2","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.M112.348540"},{"key":"e_1_3_2_38_2","volume-title":"CLSI Standard M07","year":"2018","unstructured":"Methods for dilution antimicrobial susceptibility tests for bacteria that grow aerobically. 2018. In CLSI Standard M07. Vol. 10."},{"key":"e_1_3_2_39_2","volume-title":"CLSI document M100","year":"2023","unstructured":"Clinical and Laboratory Standards Institute. Performance standards for antimicrobial susceptibility testing. 2023. In CLSI document M100. Vol. 23."},{"key":"e_1_3_2_40_2","doi-asserted-by":"publisher","DOI":"10.1007\/978-1-62703-245-2_22"},{"key":"e_1_3_2_41_2","doi-asserted-by":"publisher","DOI":"10.1128\/AAC.01004-09"},{"key":"e_1_3_2_42_2","doi-asserted-by":"publisher","DOI":"10.1128\/aac.02396-21"},{"key":"e_1_3_2_43_2","doi-asserted-by":"publisher","DOI":"10.1128\/AAC.04406-14"},{"key":"e_1_3_2_44_2","volume-title":"Scientific Computing & Instrumentation","year":"2020","unstructured":"Chemical Computing Group ULC. Molecular operating environment (MOE), 2020.0901. 2020. Scientific Computing & Instrumentation"},{"key":"e_1_3_2_45_2","doi-asserted-by":"publisher","DOI":"10.1021\/acs.jmedchem.7b00158"}],"container-title":["Antimicrobial Agents and Chemotherapy"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/journals.asm.org\/doi\/pdf\/10.1128\/aac.01511-24","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/journals.asm.org\/doi\/pdf\/10.1128\/aac.01511-24","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,4,4]],"date-time":"2025-04-04T01:11:56Z","timestamp":1743729116000},"score":1,"resource":{"primary":{"URL":"https:\/\/journals.asm.org\/doi\/10.1128\/aac.01511-24"}},"subtitle":[],"editor":[{"given":"Ryan K.","family":"Shields","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"editor"}]}],"short-title":[],"issued":{"date-parts":[[2025,3,5]]},"references-count":44,"journal-issue":{"issue":"3","published-print":{"date-parts":[[2025,3,5]]}},"alternative-id":["10.1128\/aac.01511-24"],"URL":"https:\/\/doi.org\/10.1128\/aac.01511-24","relation":{"has-preprint":[{"id-type":"doi","id":"10.1101\/2024.10.11.617870","asserted-by":"object"}]},"ISSN":["0066-4804","1098-6596"],"issn-type":[{"value":"0066-4804","type":"print"},{"value":"1098-6596","type":"electronic"}],"subject":[],"published":{"date-parts":[[2025,3,5]]},"assertion":[{"value":"2024-10-10","order":0,"name":"received","label":"Received","group":{"name":"publication_history","label":"Publication History"}},{"value":"2025-01-16","order":2,"name":"accepted","label":"Accepted","group":{"name":"publication_history","label":"Publication History"}},{"value":"2025-02-10","order":3,"name":"published","label":"Published","group":{"name":"publication_history","label":"Publication History"}}],"article-number":"e01511-24"}}