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One CAUTI pathogen,\n                      <jats:italic toggle=\"yes\">Staphylococcus aureus<\/jats:italic>\n                      , is commonly found persisting asymptomatically in the bladder of catheterized individuals, increasing these individuals\u2019 risk of developing infection. Importantly,\n                      <jats:italic toggle=\"yes\">S. aureus<\/jats:italic>\n                      is not only associated with severe symptoms during CAUTI, including bacteremia and septic shock, but it also produces a common uropathogen-associated virulence factor, urease. Despite its importance, urease has only been well-studied in another uropathogen,\n                      <jats:italic toggle=\"yes\">Proteus mirabilis<\/jats:italic>\n                      . While previous studies identified three\n                      <jats:italic toggle=\"yes\">S<\/jats:italic>\n                      .\n                      <jats:italic toggle=\"yes\">aureus<\/jats:italic>\n                      urease regulators, including CodY, CcpA, and Agr, the environmental signals required for expression and activity, and the enzyme\u2019s contribution to CAUTI have not been explored. In this study, we demonstrate that post-exponential growth and growth in the urinary tract environment significantly induce\n                      <jats:italic toggle=\"yes\">S. aureus<\/jats:italic>\n                      urease expression and activity. Additionally, we identify SigB, SaeR, and SrrA as novel regulators of urease, and further explore the role of CodY, CcpA, and Agr\u2014previously implicated in urease expression\u2014in urease regulation in the urinary tract environment. Impactfully, we found that the urease promoters of clinical isolates contain genomic changes that enhance urease expression. Furthermore, urease contributes to biofilm formation under catheterized urinary tract-like conditions\n                      <jats:italic toggle=\"yes\">in vitro<\/jats:italic>\n                      and dissemination from the bladder to the kidneys in a mouse CAUTI model. Together, our data not only provide insight into the regulatory pathway controlling\n                      <jats:italic toggle=\"yes\">S. aureus<\/jats:italic>\n                      urease but also emphasize the importance of studying these mechanisms in a model that mimics the urinary environment.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>IMPORTANCE<\/jats:title>\n                    <jats:p>\n                      In this study, we investigate how regulatory pathways coordinate the expression and activity of urease in response to environmental signals present within the catheterized urinary tract. We show that growth during the post-exponential phase and in conditions that mimic the urinary tract increases urease expression and activity. This finding challenges the dogma that\n                      <jats:italic toggle=\"yes\">Staphylococcus aureus<\/jats:italic>\n                      is a \u201cweak\u201d urease producer. We also identified three novel regulators of\n                      <jats:italic toggle=\"yes\">S. aureus<\/jats:italic>\n                      urease\u2014SigB, SrrA, and SaeR\u2014and show that their respective activation signals can modulate urease expression. Additionally, single-nucleotide changes identified in the urease regulatory pathway of clinical urinary catheter-associated isolates enhance urease expression. Finally, urease promotes biofilm formation under conditions that mimic the catheterized urinary tract and dissemination during catheter-associated urinary tract infections (CAUTIs). Our study provides insight into the complex regulatory mechanisms controlling urease in the urinary tract and highlights the role urease plays in\n                      <jats:italic toggle=\"yes\">S. aureus<\/jats:italic>\n                      CAUTI.\n                    <\/jats:p>\n                  <\/jats:sec>","DOI":"10.1128\/mbio.01624-26","type":"journal-article","created":{"date-parts":[[2026,8,5]],"date-time":"2026-08-05T13:00:17Z","timestamp":1785934817000},"update-policy":"https:\/\/doi.org\/10.1128\/asmj-crossmark-policy-page","source":"Crossref","is-referenced-by-count":0,"title":["<i>Staphylococcus aureus<\/i>\n                    urease is controlled by a complex regulatory network to promote dissemination during CAUTI"],"prefix":"10.1128","volume":"17","author":[{"given":"Jana","family":"Gomez","sequence":"first","affiliation":[{"name":"Department of Microbiology and Molecular Genetics, McGovern Medical School","place":["Houston, USA"]},{"name":"The University of Texas MD Anderson Cancer Center UTHealth Houston Graduate School of Biomedical Sciences","place":["Houston, USA"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0907-0550","authenticated-orcid":true,"given":"Jesus","family":"Duran-Ramirez","sequence":"additional","affiliation":[{"name":"Department of Microbiology and Molecular Genetics, McGovern Medical School","place":["Houston, USA"]},{"name":"The University of Texas MD Anderson Cancer Center UTHealth Houston Graduate School of Biomedical Sciences","place":["Houston, USA"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Maristhela","family":"Alvarez","sequence":"additional","affiliation":[{"name":"Department of Microbiology and Molecular Genetics, McGovern Medical School","place":["Houston, USA"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shane","family":"Cristy","sequence":"additional","affiliation":[{"name":"Department of Microbiology and Molecular Genetics, McGovern Medical School","place":["Houston, USA"]},{"name":"The University of Texas MD Anderson Cancer Center UTHealth Houston Graduate School of Biomedical Sciences","place":["Houston, USA"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0079-3261","authenticated-orcid":true,"given":"Jennifer N.","family":"Walker","sequence":"additional","affiliation":[{"name":"Department of Microbiology and Molecular Genetics, McGovern Medical School","place":["Houston, USA"]},{"name":"The University of Texas MD Anderson Cancer Center UTHealth Houston Graduate School of Biomedical Sciences","place":["Houston, USA"]},{"id":[{"id":"https:\/\/ror.org\/03gds6c39","id-type":"ROR","asserted-by":"publisher"}],"name":"Center for Infectious Diseases, Department of Epidemiology, UTHealth School of Public Health, University of Texas Health Science Center at Houston","place":["Houston, USA"]}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"235","reference":[{"key":"e_1_3_4_2_2","doi-asserted-by":"publisher","DOI":"10.1067\/mda.2003.8"},{"key":"e_1_3_4_3_2","doi-asserted-by":"publisher","DOI":"10.1001\/archinte.164.8.842"},{"key":"e_1_3_4_4_2","doi-asserted-by":"publisher","DOI":"10.1086\/597403"},{"key":"e_1_3_4_5_2","doi-asserted-by":"publisher","DOI":"10.1097\/QCO.0b013e328334dda8"},{"key":"e_1_3_4_6_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.idc.2011.09.009"},{"key":"e_1_3_4_7_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.idc.2016.07.007"},{"key":"e_1_3_4_8_2","doi-asserted-by":"publisher","DOI":"10.1038\/nrmicro3432"},{"key":"e_1_3_4_9_2","doi-asserted-by":"publisher","DOI":"10.1128\/IAI.00652-20"},{"key":"e_1_3_4_10_2","doi-asserted-by":"publisher","DOI":"10.1172\/jci.insight.144775"},{"key":"e_1_3_4_11_2","doi-asserted-by":"publisher","DOI":"10.1007\/s00345-019-03027-8"},{"key":"e_1_3_4_12_2","doi-asserted-by":"publisher","DOI":"10.1038\/s41467-023-44095-0"},{"key":"e_1_3_4_13_2","doi-asserted-by":"publisher","unstructured":"Walker J Ramirez JD Armbruster C Hanson B. 2025. 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