{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,15]],"date-time":"2026-08-15T08:09:35Z","timestamp":1786781375325,"version":"build-2736575974"},"reference-count":64,"publisher":"American Society for Microbiology","issue":"8","license":[{"start":{"date-parts":[[2026,8,5]],"date-time":"2026-08-05T00:00:00Z","timestamp":1785888000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"},{"start":{"date-parts":[[2026,8,5]],"date-time":"2026-08-05T00:00:00Z","timestamp":1785888000000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/journals.asm.org\/non-commercial-tdm-license"}],"funder":[{"DOI":"10.13039\/100000002","name":"National Institutes of Health","doi-asserted-by":"publisher","award":["1R01AI87297-01A1"],"award-info":[{"award-number":["1R01AI87297-01A1"]}],"id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["journals.asm.org"],"crossmark-restriction":true},"short-container-title":["Antimicrob Agents Chemother"],"published-print":{"date-parts":[[2026,8,5]]},"abstract":"<jats:title>ABSTRACT<\/jats:title>\n                  <jats:sec>\n                    <jats:title\/>\n                    <jats:p>\n                      Cefiderocol (CFDC) is a siderophore-conjugated cephalosporin developed to overcome multidrug resistance in gram-negative bacteria. Despite its unique iron-dependent entry mechanism, CFDC resistance has emerged in\n                      <jats:italic toggle=\"yes\">Klebsiella pneumoniae<\/jats:italic>\n                      , primarily driven by alterations in siderophore transport and \u03b2-lactamase evolution; however, the broader intrinsic resistome that supports CFDC tolerance remains incompletely defined. Here, we performed high-density transposon mutagenesis (Tn-Seq) in the epidemic ST258\n                      <jats:italic toggle=\"yes\">K. pneumoniae<\/jats:italic>\n                      to map the functional genetic landscape of CFDC susceptibility. Tn-Seq identified siderophore uptake components (\n                      <jats:italic toggle=\"yes\">tonB<\/jats:italic>\n                      and\n                      <jats:italic toggle=\"yes\">cirA<\/jats:italic>\n                      ) as the dominant determinants of CFDC resistance. In contrast, disruption of genes involved in peptidoglycan recycling (\n                      <jats:italic toggle=\"yes\">ampG<\/jats:italic>\n                      and\n                      <jats:italic toggle=\"yes\">ldcA<\/jats:italic>\n                      ), synthesis (\n                      <jats:italic toggle=\"yes\">mrcB<\/jats:italic>\n                      and\n                      <jats:italic toggle=\"yes\">lpoB<\/jats:italic>\n                      ), and enterobacterial common antigen biosynthesis (\n                      <jats:italic toggle=\"yes\">wzxE<\/jats:italic>\n                      and\n                      <jats:italic toggle=\"yes\">wzyE<\/jats:italic>\n                      ), as well as deletion of plasmid-encoded\n                      <jats:italic toggle=\"yes\">bla<\/jats:italic>\n                      <jats:sub>KPC-3<\/jats:sub>\n                      , increased CFDC susceptibility. In a CFDC-resistant \u0394\n                      <jats:italic toggle=\"yes\">tonB<\/jats:italic>\n                      strain, targeting these envelope homeostasis pathways yielded only limited resensitization relative to the siderophore-competent parental strain. Deletion of\n                      <jats:italic toggle=\"yes\">bla<\/jats:italic>\n                      <jats:sub>KPC-3<\/jats:sub>\n                      produced the greatest increase in susceptibility, reducing the CFDC MIC fourfold. This pattern is consistent with a model in which reduced CFDC influx in the \u0394\n                      <jats:italic toggle=\"yes\">tonB<\/jats:italic>\n                      background lowers intracellular drug exposure to levels at which the otherwise limited anti-CFDC activity of KPC \u03b2-lactamase becomes sufficient to drive resistance. Together, these data support a multi-layered functional network governing cefiderocol susceptibility in ST258\n                      <jats:italic toggle=\"yes\">K. pneumoniae<\/jats:italic>\n                      , in which iron-dependent drug uptake constrains intracellular exposure, while \u03b2-lactamase activity and intrinsic envelope homeostasis pathways further shape bacterial tolerance once cefiderocol enters the cell.\n                    <\/jats:p>\n                  <\/jats:sec>","DOI":"10.1128\/aac.00197-26","type":"journal-article","created":{"date-parts":[[2026,6,18]],"date-time":"2026-06-18T14:58:23Z","timestamp":1781794703000},"update-policy":"https:\/\/doi.org\/10.1128\/asmj-crossmark-policy-page","source":"Crossref","is-referenced-by-count":1,"title":["Intrinsic resistance networks shape cefiderocol susceptibility in ST258\n                    <i>Klebsiella pneumoniae<\/i>"],"prefix":"10.1128","volume":"70","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-2262-4813","authenticated-orcid":true,"given":"Kevin J.","family":"Rome","sequence":"first","affiliation":[{"name":"Center for Discovery and Innovation, Hackensack Meridian Health","place":["Nutley, USA"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0005-8209-8922","authenticated-orcid":true,"given":"Austin J.","family":"Terlecky","sequence":"additional","affiliation":[{"name":"Center for Discovery and Innovation, Hackensack Meridian Health","place":["Nutley, USA"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kelly K.","family":"Yen","sequence":"additional","affiliation":[{"name":"Center for Discovery and Innovation, Hackensack Meridian Health","place":["Nutley, USA"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tengfei","family":"Long","sequence":"additional","affiliation":[{"id":[{"id":"https:\/\/ror.org\/01y64my43","id-type":"ROR","asserted-by":"publisher"}],"name":"School of Pharmacy and Pharmaceutical Sciences, University at Buffalo","place":["Buffalo, USA"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mia J.","family":"Bucich","sequence":"additional","affiliation":[{"name":"Center for Discovery and Innovation, Hackensack Meridian Health","place":["Nutley, USA"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Klara V.","family":"Thom","sequence":"additional","affiliation":[{"name":"Center for Discovery and Innovation, Hackensack Meridian Health","place":["Nutley, USA"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Elena","family":"Shashkina","sequence":"additional","affiliation":[{"name":"Center for Discovery and Innovation, Hackensack Meridian Health","place":["Nutley, USA"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5845-2235","authenticated-orcid":true,"given":"Liang","family":"Chen","sequence":"additional","affiliation":[{"id":[{"id":"https:\/\/ror.org\/01y64my43","id-type":"ROR","asserted-by":"publisher"}],"name":"School of Pharmacy and Pharmaceutical Sciences, University at Buffalo","place":["Buffalo, USA"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"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":[{"vocabulary":"crossref","role":"author"}]}],"member":"235","reference":[{"key":"e_1_3_3_2_2","doi-asserted-by":"publisher","DOI":"10.1016\/S1473-3099(25)00118-5"},{"key":"e_1_3_3_3_2","doi-asserted-by":"publisher","DOI":"10.1016\/S0140-6736(21)02724-0"},{"key":"e_1_3_3_4_2","doi-asserted-by":"publisher","DOI":"10.1186\/s12941-017-0191-3"},{"key":"e_1_3_3_5_2","doi-asserted-by":"publisher","DOI":"10.1128\/jcm.00471-25"},{"key":"e_1_3_3_6_2","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pone.0133727"},{"key":"e_1_3_3_7_2","doi-asserted-by":"publisher","DOI":"10.1128\/mBio.01355-14"},{"key":"e_1_3_3_8_2","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.1321364111"},{"key":"e_1_3_3_9_2","doi-asserted-by":"publisher","DOI":"10.3390\/microorganisms13071697"},{"key":"e_1_3_3_10_2","doi-asserted-by":"publisher","DOI":"10.1038\/s41579-019-0159-8"},{"key":"e_1_3_3_11_2","doi-asserted-by":"publisher","DOI":"10.1093\/jac\/dkaf048"},{"key":"e_1_3_3_12_2","doi-asserted-by":"publisher","DOI":"10.1007\/s40121-021-00408-8"},{"key":"e_1_3_3_13_2","doi-asserted-by":"publisher","DOI":"10.1016\/S1473-3099(20)30796-9"},{"key":"e_1_3_3_14_2","doi-asserted-by":"publisher","DOI":"10.1093\/cid\/ciac078"},{"key":"e_1_3_3_15_2","doi-asserted-by":"publisher","DOI":"10.1128\/AAC.01405-16"},{"key":"e_1_3_3_16_2","doi-asserted-by":"publisher","DOI":"10.1093\/cid\/ciz826"},{"key":"e_1_3_3_17_2","doi-asserted-by":"publisher","DOI":"10.3390\/cimb46120846"},{"key":"e_1_3_3_18_2","doi-asserted-by":"publisher","DOI":"10.1128\/spectrum.01410-24"},{"key":"e_1_3_3_19_2","doi-asserted-by":"publisher","DOI":"10.1128\/Spectrum.01779-21"},{"key":"e_1_3_3_20_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.ijantimicag.2022.106646"},{"key":"e_1_3_3_21_2","doi-asserted-by":"publisher","DOI":"10.1007\/s10096-023-04671-0"},{"key":"e_1_3_3_22_2","doi-asserted-by":"publisher","DOI":"10.1039\/d4sc04937c"},{"key":"e_1_3_3_23_2","doi-asserted-by":"publisher","DOI":"10.1128\/aac.01548-23"},{"key":"e_1_3_3_24_2","doi-asserted-by":"publisher","DOI":"10.1007\/s10096-022-04526-0"},{"key":"e_1_3_3_25_2","doi-asserted-by":"publisher","DOI":"10.1128\/aac.01009-23"},{"key":"e_1_3_3_26_2","doi-asserted-by":"publisher","DOI":"10.1093\/jac\/dkae018"},{"key":"e_1_3_3_27_2","doi-asserted-by":"publisher","DOI":"10.1128\/spectrum.03804-25"},{"key":"e_1_3_3_28_2","doi-asserted-by":"publisher","DOI":"10.1038\/s41429-024-00762-y"},{"key":"e_1_3_3_29_2","doi-asserted-by":"publisher","DOI":"10.3389\/fmicb.2024.1355253"},{"key":"e_1_3_3_30_2","doi-asserted-by":"publisher","DOI":"10.1128\/aac.01108-23"},{"key":"e_1_3_3_31_2","doi-asserted-by":"publisher","DOI":"10.1038\/s41598-025-17044-8"},{"key":"e_1_3_3_32_2","doi-asserted-by":"publisher","DOI":"10.1039\/d5sc02122g"},{"key":"e_1_3_3_33_2","doi-asserted-by":"publisher","DOI":"10.3201\/eid3101.241426"},{"key":"e_1_3_3_34_2","doi-asserted-by":"publisher","DOI":"10.1093\/jac\/dkac221"},{"key":"e_1_3_3_35_2","doi-asserted-by":"publisher","DOI":"10.1038\/s41467-025-60828-9"},{"key":"e_1_3_3_36_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.ijantimicag.2025.107682"},{"key":"e_1_3_3_37_2","doi-asserted-by":"publisher","DOI":"10.1093\/cid\/ciab888"},{"key":"e_1_3_3_38_2","doi-asserted-by":"publisher","DOI":"10.3389\/fmicb.2021.778190"},{"key":"e_1_3_3_39_2","doi-asserted-by":"publisher","DOI":"10.1093\/jac\/dkaf462"},{"key":"e_1_3_3_40_2","doi-asserted-by":"publisher","DOI":"10.1128\/spectrum.01093-22"},{"key":"e_1_3_3_41_2","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pone.0123219"},{"key":"e_1_3_3_42_2","volume-title":"M100","author":"CLSI","year":"2023","unstructured":"CLSI. 2023. Performance standards for antimicrobial susceptibility testing. In M100, 33rd ed. Clinical and Laboratory Standards Institute, Wayne, PA.","edition":"33"},{"key":"e_1_3_3_43_2","doi-asserted-by":"publisher","DOI":"10.15252\/msb.202211398"},{"key":"e_1_3_3_44_2","doi-asserted-by":"publisher","DOI":"10.1093\/bioinformatics\/btu170"},{"key":"e_1_3_3_45_2","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pcbi.1004401"},{"key":"e_1_3_3_46_2","doi-asserted-by":"publisher","DOI":"10.1186\/1471-2105-14-303"},{"key":"e_1_3_3_47_2","doi-asserted-by":"publisher","DOI":"10.1128\/AEM.01834-18"},{"key":"e_1_3_3_48_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.mimet.2024.107047"},{"key":"e_1_3_3_49_2","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pone.0171339"},{"key":"e_1_3_3_50_2","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.2003407117"},{"key":"e_1_3_3_51_2","doi-asserted-by":"publisher","DOI":"10.1128\/mBio.01945-19"},{"key":"e_1_3_3_52_2","doi-asserted-by":"publisher","DOI":"10.1128\/JB.00352-17"},{"key":"e_1_3_3_53_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.mib.2023.102279"},{"key":"e_1_3_3_54_2","doi-asserted-by":"publisher","DOI":"10.1128\/mBio.00819-16"},{"key":"e_1_3_3_55_2","doi-asserted-by":"publisher","DOI":"10.1093\/nar\/gkae1113"},{"key":"e_1_3_3_56_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.tim.2016.12.008"},{"key":"e_1_3_3_57_2","doi-asserted-by":"publisher","DOI":"10.1128\/mr.59.4.604-622.1995"},{"key":"e_1_3_3_58_2","doi-asserted-by":"publisher","DOI":"10.1099\/00221287-132-5-1297"},{"key":"e_1_3_3_59_2","doi-asserted-by":"publisher","DOI":"10.1126\/science.1211037"},{"key":"e_1_3_3_60_2","doi-asserted-by":"publisher","DOI":"10.1126\/scisignal.aax3938"},{"key":"e_1_3_3_61_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.cmi.2025.12.010"},{"key":"e_1_3_3_62_2","doi-asserted-by":"publisher","DOI":"10.1128\/mBio.01914-20"},{"key":"e_1_3_3_63_2","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.M301750200"},{"key":"e_1_3_3_64_2","doi-asserted-by":"publisher","DOI":"10.1098\/rsob.240310"},{"key":"e_1_3_3_65_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.drup.2023.101038"}],"container-title":["Antimicrobial Agents and Chemotherapy"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/journals.asm.org\/doi\/pdf\/10.1128\/aac.00197-26","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/journals.asm.org\/doi\/pdf\/10.1128\/aac.00197-26","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,8,4]],"date-time":"2026-08-04T13:02:43Z","timestamp":1785848563000},"score":1,"resource":{"primary":{"URL":"https:\/\/journals.asm.org\/doi\/10.1128\/aac.00197-26"}},"subtitle":[],"editor":[{"given":"Alessandra","family":"Carattoli","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"editor"}]}],"short-title":[],"issued":{"date-parts":[[2026,8,5]]},"references-count":64,"journal-issue":{"issue":"8","published-print":{"date-parts":[[2026,8,5]]}},"alternative-id":["10.1128\/aac.00197-26"],"URL":"https:\/\/doi.org\/10.1128\/aac.00197-26","relation":{},"ISSN":["0066-4804","1098-6596"],"issn-type":[{"value":"0066-4804","type":"print"},{"value":"1098-6596","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,8,5]]},"assertion":[{"value":"2026-02-10","order":0,"name":"received","label":"Received","group":{"name":"publication_history","label":"Publication History"}},{"value":"2026-04-21","order":2,"name":"accepted","label":"Accepted","group":{"name":"publication_history","label":"Publication History"}},{"value":"2026-06-18","order":3,"name":"published","label":"Published","group":{"name":"publication_history","label":"Publication History"}}],"article-number":"e00197-26"}}