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However, reduced susceptibility to cefiderocol in NDM-producing strains is increasingly observed. This study elucidated the mechanism of high-level cefiderocol resistance in a clinical\n                      <jats:italic toggle=\"yes\">Klebsiella pneumoniae<\/jats:italic>\n                      strain (KP5663, ST147-KL64) producing NDM-5, which emerged without prior drug exposure. Whole-genome sequencing identified, alongside\n                      <jats:italic toggle=\"yes\">bla<\/jats:italic>\n                      <jats:sub>NDM-5<\/jats:sub>\n                      and\n                      <jats:italic toggle=\"yes\">ompK35<\/jats:italic>\n                      \/\n                      <jats:italic toggle=\"yes\">ompK36<\/jats:italic>\n                      porin deficiencies, a novel \u03b2-lactamase gene variant,\n                      <jats:italic toggle=\"yes\">bla<\/jats:italic>\n                      <jats:sub>SHV-248<\/jats:sub>\n                      . Functional characterization revealed that SHV-248 exhibited a moderately higher affinity for cefiderocol (binding energy: \u22125.15 kcal\/mol) and a 1.6-fold greater hydrolytic activity against nitrocefin compared to SHV-12. Consistent with this, heterologous expression of\n                      <jats:italic toggle=\"yes\">bla<\/jats:italic>\n                      <jats:sub>SHV-248<\/jats:sub>\n                      , but not\n                      <jats:italic toggle=\"yes\">bla<\/jats:italic>\n                      <jats:sub>SHV-12<\/jats:sub>\n                      , increased the cefiderocol minimum inhibitory concentration (MIC) by fourfold, although the MIC remained within the susceptible range. Critically, genetic complementation demonstrated that restoring functional\n                      <jats:italic toggle=\"yes\">ompK35<\/jats:italic>\n                      alone reduced the cefiderocol MIC of KP5663 by 16-fold, whereas complementation with\n                      <jats:italic toggle=\"yes\">ompK36<\/jats:italic>\n                      had no effect. These findings define a novel synergistic triad wherein the combined, rather than individual, action of\n                      <jats:italic toggle=\"yes\">bla<\/jats:italic>\n                      <jats:sub>NDM-5<\/jats:sub>\n                      , the novel variant\n                      <jats:italic toggle=\"yes\">bla<\/jats:italic>\n                      <jats:sub>SHV-248<\/jats:sub>\n                      , and porin deficiency (primarily\n                      <jats:italic toggle=\"yes\">ompK35<\/jats:italic>\n                      ) is necessary and sufficient for high-level cefiderocol resistance.\n                    <\/jats:p>\n                    <jats:sec>\n                      <jats:title>IMPORTANCE<\/jats:title>\n                      <jats:p>\n                        This study identifies a novel SHV variant and, more importantly, delineates a distinct \u201ckey determinant combination\u201d model for cefiderocol resistance. This model does not rely on exceptional enzyme overproduction but on the convergence of three clinically relevant factors: a transmissible\n                        <jats:italic toggle=\"yes\">bla<\/jats:italic>\n                        <jats:sub>NDM-5<\/jats:sub>\n                        , a chromosomally evolving SHV variant with incremental efficiency gains, and frequent porin loss. It underscores that, for NDM-producing\n                        <jats:italic toggle=\"yes\">Klebsiella pneumoniae<\/jats:italic>\n                        , risk assessment must evolve to evaluate porin status alongside \u03b2-lactamase profiles, as even modestly more efficient enzymes like SHV-248 can become decisive factors within a permissive genetic background.\n                      <\/jats:p>\n                    <\/jats:sec>\n                  <\/jats:sec>","DOI":"10.1128\/spectrum.00026-26","type":"journal-article","created":{"date-parts":[[2026,4,30]],"date-time":"2026-04-30T13:03:21Z","timestamp":1777554201000},"update-policy":"https:\/\/doi.org\/10.1128\/asmj-crossmark-policy-page","source":"Crossref","is-referenced-by-count":2,"title":["Combinatorial effects of a novel SHV-248 variant, NDM-5, and\n                    <i>ompK35<\/i>\n                    deficiency drive high-level cefiderocol resistance in\n                    <i>Klebsiella pneumoniae<\/i>"],"prefix":"10.1128","volume":"14","author":[{"ORCID":"https:\/\/orcid.org\/0009-0004-5687-8258","authenticated-orcid":false,"given":"Chuwen","family":"Zhao","sequence":"first","affiliation":[{"id":[{"id":"https:\/\/ror.org\/00g3pqv36","id-type":"ROR","asserted-by":"publisher"}],"name":"Department of Clinical Laboratory, The First Affiliated Hospital, Jiangxi Medical College, Nanchang University","place":["Nanchang, China"]},{"id":[{"id":"https:\/\/ror.org\/042v6xz23","id-type":"ROR","asserted-by":"publisher"}],"name":"First Clinical Medical College, Nanchang University","place":["Nanchang, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yuxuan","family":"Liu","sequence":"additional","affiliation":[{"id":[{"id":"https:\/\/ror.org\/00g3pqv36","id-type":"ROR","asserted-by":"publisher"}],"name":"Department of Clinical Laboratory, The First Affiliated Hospital, Jiangxi Medical College, Nanchang University","place":["Nanchang, 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