{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,4,18]],"date-time":"2026-04-18T08:20:04Z","timestamp":1776500404331,"version":"3.51.2"},"reference-count":44,"publisher":"American Society for Microbiology","issue":"2","license":[{"start":{"date-parts":[[2025,2,13]],"date-time":"2025-02-13T00:00:00Z","timestamp":1739404800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"},{"start":{"date-parts":[[2025,2,13]],"date-time":"2025-02-13T00:00:00Z","timestamp":1739404800000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/journals.asm.org\/non-commercial-tdm-license"}],"funder":[{"DOI":"10.13039\/100000897","name":"Cystic Fibrosis Foundation","doi-asserted-by":"crossref","award":["SHIN24F0"],"award-info":[{"award-number":["SHIN24F0"]}],"id":[{"id":"10.13039\/100000897","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":[[2025,2,13]]},"abstract":"<jats:title>ABSTRACT<\/jats:title>\n          <jats:sec>\n            <jats:title\/>\n            <jats:p>\n              <jats:italic>Mycobacterium abscessus<\/jats:italic>\n              (\n              <jats:italic>Mab<\/jats:italic>\n              ) presents significant clinical challenges. This study evaluated the synergistic effects of a \u03b2-lactam and \u03b2-lactamase inhibitor combination against\n              <jats:italic>Mab<\/jats:italic>\n              and explored the underlying mechanisms. Synergy was assessed through MIC tests and time-kill studies, and binding affinities of nine \u03b2-lactams and BLIs to eight target receptors (L,D-transpeptidases [LDT] 1\u20135, D,D-carboxypeptidase, penicillin-binding protein [PBP] B, and PBP-lipo) were assessed using mass spectrometry and kinetic studies. Thermal stability and morphological changes were determined. Imipenem demonstrated high binding affinity to LDTs and PBPs, with extremely low inhibition constants (\n              <jats:italic>\n                K\n                <jats:sub>i<\/jats:sub>\n              <\/jats:italic>\n              <jats:sub>\n                ,\n                <jats:italic>app<\/jats:italic>\n              <\/jats:sub>\n              ; \u22640.002 mg\/L for LDT1\u22122, \u22640.6 mg\/L for PBPs), while cephalosporins, sulopenem, tebipenem, and amoxicillin exhibited moderate to low binding affinity. Durlobactam inactivated Bla\n              <jats:sub>Mab<\/jats:sub>\n              and LDT\/PBPs more potently than avibactam. The\n              <jats:italic>\n                K\n                <jats:sub>i,app<\/jats:sub>\n              <\/jats:italic>\n              s of durlobactam for PBP B, PBP-lipo, and LDT2 were below clinically achievable unbound concentrations, while avibactam\u2019s\n              <jats:italic>\n                K\n                <jats:sub>i,app<\/jats:sub>\n              <\/jats:italic>\n              for LDT\/PBPs exceeded the clinical concentrations. Single \u03b2-lactam treatments resulted in minimal killing (~1 log\n              <jats:sub>10<\/jats:sub>\n              reduction). Although avibactam yielded no effect, combinations with avibactam showed a significant reduction (~4 log\n              <jats:sub>10<\/jats:sub>\n              CFU\/mL). Durlobactam alone showed ~2 log\n              <jats:sub>10<\/jats:sub>\n              reduction, and when combined with imipenem or two \u03b2-lactams, durlobactam achieved near-eradication of\n              <jats:italic>Mab<\/jats:italic>\n              , surpassing the current therapy (amikacin + clarithromycin + imipenem\/cefoxitin). Inactivation of PBP-lipo by sulopenem, imipenem, durlobactam, and amoxicillin (with avibactam) led to morphological changes, showing filaments. This study demonstrates the mechanistic basis of combinations therapy, particularly imipenem + durlobactam, in overcoming \u03b2-lactam resistance in\n              <jats:italic>Mab<\/jats:italic>\n              .\n            <\/jats:p>\n          <\/jats:sec>","DOI":"10.1128\/aac.01174-24","type":"journal-article","created":{"date-parts":[[2024,12,23]],"date-time":"2024-12-23T14:01:12Z","timestamp":1734962472000},"update-policy":"https:\/\/doi.org\/10.1128\/asmj-crossmark-policy-page","source":"Crossref","is-referenced-by-count":17,"title":["Durlobactam in combination with \u03b2-lactams to combat\n            <i>Mycobacterium abscessus<\/i>"],"prefix":"10.1128","volume":"69","author":[{"ORCID":"https:\/\/orcid.org\/0009-0006-2472-3264","authenticated-orcid":true,"given":"Eunjeong","family":"Shin","sequence":"first","affiliation":[{"name":"Louis Stokes Cleveland VA Medical Center","place":["Cleveland, USA"]},{"name":"Department of Medicine, Case Western Reserve University School of Medicine","place":["Cleveland, USA"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3272-7231","authenticated-orcid":true,"given":"Khalid M.","family":"Dousa","sequence":"additional","affiliation":[{"name":"Louis Stokes Cleveland VA Medical Center","place":["Cleveland, USA"]},{"name":"Department of Medicine, Case Western Reserve University School of Medicine","place":["Cleveland, USA"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Magdalena A.","family":"Taracila","sequence":"additional","affiliation":[{"name":"Louis Stokes Cleveland VA Medical Center","place":["Cleveland, USA"]},{"name":"Department of Medicine, Case Western Reserve University School of Medicine","place":["Cleveland, USA"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Christopher R.","family":"Bethel","sequence":"additional","affiliation":[{"name":"Louis Stokes Cleveland VA Medical Center","place":["Cleveland, USA"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Mary","family":"Nantongo","sequence":"additional","affiliation":[{"name":"Department of Molecular Biology and Microbiology, Case Western Reserve University School of Medicine","place":["Cleveland, USA"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5738-2976","authenticated-orcid":true,"given":"David C.","family":"Nguyen","sequence":"additional","affiliation":[{"name":"Division of Infectious Diseases, Department of Pediatrics and Division of Infectious Diseases, and Department of Internal Medicine, Rush University Medical Center","place":["Chicago, USA"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Chidiebere","family":"Akusobi","sequence":"additional","affiliation":[{"name":"Department of Immunology and Infectious Diseases, Harvard T. H. Chan School of Public Health","place":["Boston, USA"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Sebastian G.","family":"Kurz","sequence":"additional","affiliation":[{"name":"School of Medicine, Yale University","place":["New Haven, USA"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Mark S.","family":"Plummer","sequence":"additional","affiliation":[{"name":"Biopharmaworks","place":["Groton, USA"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Charles L.","family":"Daley","sequence":"additional","affiliation":[{"name":"Division of Mycobacterial and Respiratory Infections, National Jewish Health","place":["Denver, USA"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Steven M.","family":"Holland","sequence":"additional","affiliation":[{"name":"Laboratory of Clinical Immunology and Microbiology, National Institutes of Health, National Institute of Allergy and Infectious Diseases","place":["Bethesda, USA"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5120-962X","authenticated-orcid":true,"given":"Eric J.","family":"Rubin","sequence":"additional","affiliation":[{"name":"Department of Immunology and Infectious Diseases, Harvard T. H. Chan School of Public Health","place":["Boston, USA"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"J\u00fcrgen B.","family":"Bulitta","sequence":"additional","affiliation":[{"name":"Department of Pharmacotherapy and Translational Research, College of Pharmacy, University of Florida","place":["Orlando, USA"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"W. Henry","family":"Boom","sequence":"additional","affiliation":[{"name":"Department of Medicine, Case Western Reserve University School of Medicine","place":["Cleveland, USA"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0243-131X","authenticated-orcid":true,"given":"Barry N.","family":"Kreiswirth","sequence":"additional","affiliation":[{"name":"Center for Discovery and Innovation, Hackensack Meridian Health","place":["Nutley, USA"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3299-894X","authenticated-orcid":true,"given":"Robert A.","family":"Bonomo","sequence":"additional","affiliation":[{"name":"Louis Stokes Cleveland VA Medical Center","place":["Cleveland, USA"]},{"name":"Department of Medicine, Case Western Reserve University School of Medicine","place":["Cleveland, USA"]},{"name":"Department of Molecular Biology and Microbiology, Case Western Reserve University School of Medicine","place":["Cleveland, USA"]},{"name":"CWRU-Cleveland VAMC Center for Antibiotic Resistance and Epidemiology (Case VA CARES)","place":["Cleveland, USA"]},{"name":"Departments of Biochemistry, Pharmacology, and Proteomics and Bioinformatics, Case Western Reserve University","place":["Cleveland, USA"]},{"name":"Department of Pharmacology, School of Medicine, Case Western Reserve University","place":["Cleveland, USA"]}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"235","reference":[{"key":"e_1_3_3_2_2","doi-asserted-by":"publisher","DOI":"10.1093\/jac\/dkr578"},{"key":"e_1_3_3_3_2","doi-asserted-by":"publisher","DOI":"10.1183\/13993003.00798-2019"},{"key":"e_1_3_3_4_2","doi-asserted-by":"publisher","DOI":"10.1097\/QCO.0000000000000104"},{"key":"e_1_3_3_5_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.jcf.2009.12.001"},{"key":"e_1_3_3_6_2","doi-asserted-by":"publisher","DOI":"10.1093\/jac\/dks279"},{"key":"e_1_3_3_7_2","doi-asserted-by":"publisher","DOI":"10.1128\/AAC.01275-08"},{"key":"e_1_3_3_8_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.chest.2021.07.035"},{"key":"e_1_3_3_9_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.idc.2020.06.001"},{"key":"e_1_3_3_10_2","doi-asserted-by":"publisher","DOI":"10.1183\/13993003.00535-2020"},{"key":"e_1_3_3_11_2","doi-asserted-by":"publisher","DOI":"10.1128\/AAC.01206-17"},{"key":"e_1_3_3_12_2","doi-asserted-by":"publisher","DOI":"10.1097\/00000542-197809000-00018"},{"key":"e_1_3_3_13_2","doi-asserted-by":"publisher","DOI":"10.1111\/j.1365-2125.2011.03991.x"},{"key":"e_1_3_3_14_2","doi-asserted-by":"publisher","DOI":"10.1128\/AAC.00425-19"},{"key":"e_1_3_3_15_2","doi-asserted-by":"publisher","DOI":"10.3389\/fmicb.2018.02273"},{"key":"e_1_3_3_16_2","doi-asserted-by":"publisher","DOI":"10.1128\/JB.00606-10"},{"key":"e_1_3_3_17_2","doi-asserted-by":"publisher","DOI":"10.1128\/jb.00046-22"},{"key":"e_1_3_3_18_2","doi-asserted-by":"publisher","DOI":"10.1128\/aac.00093-22"},{"key":"e_1_3_3_19_2","doi-asserted-by":"publisher","DOI":"10.7554\/eLife.71947"},{"key":"e_1_3_3_20_2","doi-asserted-by":"publisher","DOI":"10.1128\/AAC.01956-20"},{"key":"e_1_3_3_21_2","doi-asserted-by":"publisher","DOI":"10.1128\/AAC.00098-20"},{"key":"e_1_3_3_22_2","doi-asserted-by":"publisher","DOI":"10.1177\/10600280211031390"},{"key":"e_1_3_3_23_2","doi-asserted-by":"publisher","DOI":"10.1093\/jac\/dkt410"},{"key":"e_1_3_3_24_2","doi-asserted-by":"publisher","DOI":"10.1128\/mbio.00609-24"},{"key":"e_1_3_3_25_2","doi-asserted-by":"publisher","DOI":"10.1128\/mbio.03529-21"},{"key":"e_1_3_3_26_2","doi-asserted-by":"publisher","DOI":"10.1186\/s13756-018-0448-4"},{"key":"e_1_3_3_27_2","doi-asserted-by":"publisher","DOI":"10.1128\/AAC.05080-14"},{"key":"e_1_3_3_28_2","doi-asserted-by":"publisher","DOI":"10.1128\/AAC.02440-16"},{"key":"e_1_3_3_29_2","doi-asserted-by":"publisher","DOI":"10.1128\/AAC.01915-18"},{"key":"e_1_3_3_30_2","doi-asserted-by":"publisher","DOI":"10.1128\/AAC.00733-19"},{"key":"e_1_3_3_31_2","doi-asserted-by":"publisher","DOI":"10.1128\/AAC.02282-15"},{"key":"e_1_3_3_32_2","doi-asserted-by":"publisher","DOI":"10.1128\/AAC.01353-17"},{"key":"e_1_3_3_33_2","doi-asserted-by":"publisher","DOI":"10.1101\/cshperspect.a025247"},{"key":"e_1_3_3_34_2","doi-asserted-by":"crossref","unstructured":"Woods GL Brown-Elliott BA Conville PS Desmond EP Hall GS Lin G Pfyffer GE Ridderhof JC Siddiqi SH Wallace RJ Warren NG Witebsky FG. 2011. 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