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In Kp, PNAG synthesis is mediated by the\n                      <jats:italic toggle=\"yes\">pgaABCD<\/jats:italic>\n                      operon, yet its lineage-specific regulation remains incompletely understood. Using a comparative genomics approach to interrogate the\n                      <jats:italic toggle=\"yes\">pgaABCD<\/jats:italic>\n                      locus across the high-risk clonal Kp complex 258 (CC258) lineage, we identified a previously uncharacterized positive transcriptional regulator located immediately upstream of\n                      <jats:italic toggle=\"yes\">pgaA<\/jats:italic>\n                      , which we designate\n                      <jats:italic toggle=\"yes\">pgaR<\/jats:italic>\n                      . Phylogenetic analysis revealed recurrent evolutionary events affecting this regulatory region, including repeated deletion or truncation of\n                      <jats:italic toggle=\"yes\">pgaR<\/jats:italic>\n                      and a G &gt; A substitution upstream of the\n                      <jats:italic toggle=\"yes\">pgaR<\/jats:italic>\n                      start codon. Functional characterization demonstrated that loss of\n                      <jats:italic toggle=\"yes\">pgaR<\/jats:italic>\n                      abolishes\n                      <jats:italic toggle=\"yes\">pgaABCD<\/jats:italic>\n                      expression and PNAG production, whereas the upstream G &gt; A substitution drives PNAG hyperproduction. Under\n                      <jats:italic toggle=\"yes\">in vitro<\/jats:italic>\n                      growth conditions, Kp produce extensive extracellular PNAG networks. Using a prototype hypervirulent strain to model the role of PNAG\n                      <jats:italic toggle=\"yes\">in vivo<\/jats:italic>\n                      indicated that it is dispensable for virulence in murine pneumonia and peritonitis models. In contrast, PNAG hyper-production significantly attenuated virulence and reduced disease severity. Collectively, these findings identify PgaR as a novel upstream gene regulator of the\n                      <jats:italic toggle=\"yes\">pgaABCD<\/jats:italic>\n                      operon and reveal a previously unrecognized lineage-specific layer of PNAG regulation in Kp. This demonstrates that opposing PNAG phenotypes, loss and hyper-production, have independently and repeatedly emerged among clinical CC258 isolates, highlighting selective pressures acting on this locus.\n                    <\/jats:p>\n                  <\/jats:sec>","DOI":"10.1128\/iai.00451-26","type":"journal-article","created":{"date-parts":[[2026,9,24]],"date-time":"2026-09-24T13:16:50Z","timestamp":1790255810000},"update-policy":"https:\/\/doi.org\/10.1128\/asmj-crossmark-policy-page","source":"Crossref","is-referenced-by-count":0,"title":["<i>PgaR<\/i>\n                    is a positive regulator of the\n                    <i>pgaABCD<\/i>\n                    biosynthetic operon in\n                    <i>Klebsiella<\/i>\n                    pneumoniae"],"prefix":"10.1128","volume":"94","author":[{"given":"Jonathan","family":"Bradshaw","sequence":"first","affiliation":[{"id":[{"id":"https:\/\/ror.org\/041kmwe10","id-type":"ROR","asserted-by":"publisher"}],"name":"Department of Life Sciences, Imperial College London","place":["London, United Kingdom"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5847-4167","authenticated-orcid":false,"given":"Julia","family":"Sanchez-Garrido","sequence":"additional","affiliation":[{"id":[{"id":"https:\/\/ror.org\/041kmwe10","id-type":"ROR","asserted-by":"publisher"}],"name":"Department of Life Sciences, Imperial College London","place":["London, United Kingdom"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sophia","family":"David","sequence":"additional","affiliation":[{"id":[{"id":"https:\/\/ror.org\/052gg0110","id-type":"ROR","asserted-by":"publisher"}],"name":"Centre for Genomic Pathogen Surveillance, Pandemic Sciences Institute, University of Oxford","place":["Oxford, United Kingdom"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mariagrazia","family":"Pizza","sequence":"additional","affiliation":[{"id":[{"id":"https:\/\/ror.org\/041kmwe10","id-type":"ROR","asserted-by":"publisher"}],"name":"Department of Life Sciences, Imperial College London","place":["London, United Kingdom"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Immaculada","family":"Margarit Ros","sequence":"additional","affiliation":[{"name":"GSK","place":["Siena, Italy"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Maria Rosaria","family":"Romano","sequence":"additional","affiliation":[{"name":"GSK","place":["Siena, Italy"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8437-6731","authenticated-orcid":true,"given":"Joshua L. 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