{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,11]],"date-time":"2026-09-11T14:10:09Z","timestamp":1789135809178,"version":"build-2803163510"},"reference-count":35,"publisher":"American Chemical Society (ACS)","issue":"9","license":[{"start":{"date-parts":[[2026,8,21]],"date-time":"2026-08-21T00:00:00Z","timestamp":1787270400000},"content-version":"stm-asf","delay-in-days":0,"URL":"https:\/\/doi.org\/10.15223\/policy-029"},{"start":{"date-parts":[[2026,8,21]],"date-time":"2026-08-21T00:00:00Z","timestamp":1787270400000},"content-version":"stm-asf","delay-in-days":0,"URL":"https:\/\/doi.org\/10.15223\/policy-037"},{"start":{"date-parts":[[2026,8,21]],"date-time":"2026-08-21T00:00:00Z","timestamp":1787270400000},"content-version":"stm-asf","delay-in-days":0,"URL":"https:\/\/doi.org\/10.15223\/policy-045"}],"funder":[{"DOI":"10.13039\/100000057","name":"National Institute of General Medical Sciences","doi-asserted-by":"publisher","award":["R01 GM128439A1"],"award-info":[{"award-number":["R01 GM128439A1"]}],"id":[{"id":"10.13039\/100000057","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000057","name":"National Institute of General Medical Sciences","doi-asserted-by":"publisher","award":["R35 GM15330"],"award-info":[{"award-number":["R35 GM15330"]}],"id":[{"id":"10.13039\/100000057","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2026,9,11]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:p>Patients suffering from Urinary Tract Infections (UTIs) are faced with multidrug resistance and a lack of treatment options. An alternative strategy to traditional bactericidal drug design is to disarm pathogenic bacteria by targeting the regulation of virulence factors. Small-molecule CpxRA phosphatase inhibitor compound 26, hereafter referred to as Cpx26, has shown efficacy in a murine UTI model; however, the impact of pharmacological modulation of CpxRA on bacterial physiology is undefined. Herein, we report the activity of Cpx26 in phenotypic assays to provide insight into its mechanism of action and antivirulence properties. Cpx26 significantly inhibited swimming motility, biofilm formation, and adhesion to bladder epithelial cells at concentrations &amp;gt;60-fold below its MIC. Combination with first-line UTI antibiotics was explored, and synergy was observed with trimethoprim\/sulfamethoxazole and fosfomycin, implying potential clinical benefit. This work highlights the potential of antivirulence therapies for prevalent infections such as UTIs.<\/jats:p>","DOI":"10.1021\/acsinfecdis.6c00457","type":"journal-article","created":{"date-parts":[[2026,8,22]],"date-time":"2026-08-22T06:16:57Z","timestamp":1787379417000},"page":"2995-3001","source":"Crossref","is-referenced-by-count":0,"title":["Phenotypic Effects\nof a Small Molecule CpxA Phosphatase\nInhibitor on Uropathogenic\n                    <i>Escherichia coli<\/i>"],"prefix":"10.1021","volume":"12","author":[{"ORCID":"https:\/\/orcid.org\/0009-0003-8330-9694","authenticated-orcid":true,"given":"Alexis M.","family":"Stoorza","sequence":"first","affiliation":[{"name":"University of Minnesota , , , ,","place":["Minneapolis, Minnesota, United States, 55414"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8287-8893","authenticated-orcid":true,"given":"Erin E.","family":"Carlson","sequence":"additional","affiliation":[{"name":"University of Minnesota , , , ,","place":["Minneapolis, Minnesota, United States, 55414"]},{"name":"University of Minnesota , , , ,","place":["Minneapolis, Minnesota, United States, 55455"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3130-9890","authenticated-orcid":true,"given":"Adam S.","family":"Duerfeldt","sequence":"additional","affiliation":[{"name":"University of Minnesota , , , ,","place":["Minneapolis, Minnesota, United States, 55414"]}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"316","published-online":{"date-parts":[[2026,8,21]]},"reference":[{"issue":"5","key":"2026091109072629800_cit1","doi-asserted-by":"publisher","first-page":"269","DOI":"10.1038\/nrmicro3432","article-title":"Urinary Tract Infections:\nEpidemiology, Mechanisms of Infection and Treatment Options","volume":"13","author":"Flores-Mireles","year":"2015","journal-title":"Nat. Rev. Microbiol."},{"issue":"6","key":"2026091109072629800_cit2","doi-asserted-by":"publisher","first-page":"e1344","DOI":"10.1093\/infdis\/jiae233","article-title":"Antibiotic\nResistance of Urinary Tract Infection Recurrences in a Large Integrated\nUS Healthcare System","volume":"230","author":"Ku","year":"2024","journal-title":"J. Infect. Dis."},{"issue":"1","key":"2026091109072629800_cit3","doi-asserted-by":"publisher","first-page":"1232","DOI":"10.1186\/s12879-021-06939-2","article-title":"Clinical Impact of\nMultidrug-Resistant Bacteria in Older Hospitalized Patients with Community-Acquired\nUrinary Tract Infection","volume":"21","author":"Madrazo","year":"2021","journal-title":"BMC Infect. Dis."},{"issue":"20","key":"2026091109072629800_cit4","doi-asserted-by":"publisher","first-page":"9390","DOI":"10.1021\/acs.jmedchem.6b00948","article-title":"Antivirulence\nC-Mannosides as Antibiotic-Sparing, Oral Therapeutics for Urinary\nTract Infections","volume":"59","author":"Mydock-McGrane","year":"2016","journal-title":"J. Med. Chem."},{"key":"2026091109072629800_cit5","doi-asserted-by":"publisher","first-page":"107","DOI":"10.1016\/j.mib.2021.03.007","article-title":"Targeting\na Highly Conserved Domain in Bacterial Histidine\nKinases to Generate Inhibitors with Broad Spectrum Activity","volume":"61","author":"Fihn","year":"2021","journal-title":"Curr. Opin. Microbiol."},{"issue":"1","key":"2026091109072629800_cit6","doi-asserted-by":"publisher","first-page":"183","DOI":"10.1146\/annurev.biochem.69.1.183","article-title":"Two-Component Signal\nTransduction","volume":"69","author":"Stock","year":"2000","journal-title":"Annu. Rev. Biochem."},{"issue":"9","key":"2026091109072629800_cit7","doi-asserted-by":"publisher","first-page":"3898","DOI":"10.1128\/IAI.00432-10","article-title":"Activation of the\nCpxRA System by Deletion of cpxA Impairs the Ability of Haemophilus\nDucreyi To Infect Humans","volume":"78","author":"Spinola","year":"2010","journal-title":"Infect. Immun."},{"issue":"2","key":"2026091109072629800_cit8","doi-asserted-by":"publisher","first-page":"e02430","DOI":"10.1128\/spectrum.02430-21","article-title":"CpxA Phosphatase Inhibitor Activates\nCpxRA and Is a Potential Treatment for Uropathogenic Escherichia Coli\nin a Murine Model of Infection","volume":"10","author":"Fortney","year":"2022","journal-title":"Microbiol. Spectr."},{"issue":"9","key":"2026091109072629800_cit9","doi-asserted-by":"publisher","DOI":"10.1128\/iai.00307-17","article-title":"Both MisR (CpxR) and MisS (CpxA)\nAre Required for Neisseria Gonorrhoeae Infection in a Murine Model\nof Lower Genital Tract Infection","volume":"85","author":"Gangaiah","year":"2017","journal-title":"Infect. Immun."},{"issue":"7","key":"2026091109072629800_cit10","doi-asserted-by":"publisher","first-page":"3789","DOI":"10.1128\/AAC.00236-15","article-title":"Development and Validation of a High-Throughput Cell-Based\nScreen To Identify Activators of a Bacterial Two-Component Signal\nTransduction System","volume":"59","author":"van Rensburg","year":"2015","journal-title":"Antimicrob. Agents Chemother."},{"issue":"14","key":"2026091109072629800_cit11","doi-asserted-by":"publisher","first-page":"1836","DOI":"10.1016\/j.bmcl.2019.05.003","article-title":"First-Generation\nStructure-Activity Relationship Studies of 2,3,4,9-Tetrahydro-1H-Carbazol-1-Amines\nas CpxA Phosphatase Inhibitors","volume":"29","author":"Li","year":"2019","journal-title":"Bioorg. Med.\nChem. Lett."},{"issue":"3","key":"2026091109072629800_cit12","doi-asserted-by":"publisher","first-page":"e00798","DOI":"10.1128\/IAI.00798-17","article-title":"Evaluation\nof CpxRA as a Therapeutic Target for Uropathogenic Escherichia Coli\nInfections","volume":"86","author":"Dbeibo","year":"2018","journal-title":"Infect. Immun."},{"key":"2026091109072629800_cit13","doi-asserted-by":"publisher","first-page":"4","DOI":"10.1128\/microbiolspec.UTI-0015-2012","article-title":"Virulence and\nFitness Determinants of Uropathogenic\nEscherichia Coli","volume":"3","author":"Subashchandrabose","year":"2015","journal-title":"Microbiol. Spectr."},{"issue":"12","key":"2026091109072629800_cit14","doi-asserted-by":"publisher","first-page":"2755","DOI":"10.1128\/JB.00105-13","article-title":"The Escherichia\nColi Cpx Envelope\nStress Response Regulates Genes of Diverse Function That Impact Antibiotic\nResistance and Membrane Integrity","volume":"195","author":"Raivio","year":"2013","journal-title":"J. Bacteriol."},{"issue":"11","key":"2026091109072629800_cit15","doi-asserted-by":"publisher","first-page":"7644","DOI":"10.1128\/IAI.73.11.7644-7656.2005","article-title":"Role of Motility\nin the Colonization of Uropathogenic Escherichia Coli in the Urinary\nTract","volume":"73","author":"Lane","year":"2005","journal-title":"Infect. Immun."},{"issue":"21","key":"2026091109072629800_cit16","doi-asserted-by":"publisher","first-page":"6772","DOI":"10.1128\/JB.181.21.6772-6778.1999","article-title":"The CpxRA Signal Transduction System\nofEscherichia Coli: Growth-Related Autoactivation and Control of Unanticipated\nTarget Operons","volume":"181","author":"De Wulf","year":"1999","journal-title":"J. Bacteriol."},{"issue":"3","key":"2026091109072629800_cit17","doi-asserted-by":"publisher","first-page":"707","DOI":"10.1128\/JB.00938-13","article-title":"Repression\nof Flagellar Genes in Exponential Phase by CsgD and CpxR, Two Crucial\nModulators of Escherichia Coli Biofilm Formation","volume":"196","author":"Dudin","year":"2014","journal-title":"J. Bacteriol."},{"issue":"2","key":"2026091109072629800_cit18","doi-asserted-by":"publisher","first-page":"736","DOI":"10.1128\/jb.159.2.736-744.1984","article-title":"Organization and Expression of Genes Responsible for\nType 1 Piliation in Escherichia Coli","volume":"159","author":"Orndorff","year":"1984","journal-title":"J. Bacteriol."},{"issue":"12","key":"2026091109072629800_cit19","doi-asserted-by":"publisher","first-page":"2803","DOI":"10.1093\/emboj\/19.12.2803","article-title":"Type 1\nPilus-mediated Bacterial Invasion of Bladder Epithelial Cells","volume":"19","author":"Martinez","year":"2000","journal-title":"EMBO J."},{"issue":"4","key":"2026091109072629800_cit20","doi-asserted-by":"publisher","first-page":"2287","DOI":"10.1073\/pnas.042521699","article-title":"Surface Sensing\nand Adhesion of Escherichia Coli Controlled\nby the Cpx-Signaling Pathway","volume":"99","author":"Otto","year":"2002","journal-title":"Proc. Natl. Acad.\nSci. U. S. A."},{"issue":"10","key":"2026091109072629800_cit21","doi-asserted-by":"publisher","first-page":"3582","DOI":"10.1128\/AAC.00506-07","article-title":"High-Throughput Screens for Small-Molecule Inhibitors\nof Pseudomonas Aeruginosa Biofilm Development","volume":"51","author":"Junker","year":"2007","journal-title":"Antimicrob. Agents and Chemother."},{"issue":"34","key":"2026091109072629800_cit22","doi-asserted-by":"publisher","first-page":"10745","DOI":"10.1002\/chem.200801419","article-title":"Synthesis and Antibiofilm\nActivity of a Second-Generation Reverse-Amide Oroidin Library: A Structure\u2013Activity\nRelationship Study","volume":"14","author":"Ballard","year":"2008","journal-title":"Chem. \u2013 Eur. J."},{"key":"2026091109072629800_cit23","article-title":"Antimicrobial\nResistance: Tackling a Crisis for the Health and Wealth of Nations","author":"Neill","year":"2014","journal-title":"Review on Antimicrobial Resistance."},{"issue":"7","key":"2026091109072629800_cit24","doi-asserted-by":"publisher","first-page":"457","DOI":"10.1038\/nrd.2017.23","article-title":"Different\nDrugs for Bad Bugs: Antivirulence\nStrategies in the Age of Antibiotic Resistance","volume":"16","author":"Dickey","year":"2017","journal-title":"Nat. Rev. Drug Discovery"},{"issue":"8","key":"2026091109072629800_cit25","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pbio.3000805","article-title":"Combining Antibiotics with Antivirulence\nCompounds\nCan Have Synergistic Effects and Reverse Selection for Antibiotic\nResistance in Pseudomonas Aeruginosa","volume":"18","author":"Rezzoagli","year":"2020","journal-title":"PLoS Biol."},{"issue":"6","key":"2026091109072629800_cit26","doi-asserted-by":"publisher","first-page":"819","DOI":"10.3390\/antibiotics11060819","article-title":"Antivirulence\nAgent as an Adjuvant of \u03b2-Lactam\nAntibiotics in Treating Staphylococcal Infections","volume":"11","author":"Gao","year":"2022","journal-title":"Antibiotics"},{"key":"2026091109072629800_cit27","doi-asserted-by":"publisher","first-page":"15","DOI":"10.3389\/fcimb.2025.1526246","article-title":"A Chionodracine-Derived\nPeptide, KHS-Cnd, as an Anti-Virulence Agent against Multidrug-Resistant\nAcinetobacter Baumannii Clinical Strains","volume":"15","author":"Artini","year":"2025","journal-title":"Front.\nCell. Infect. Microbiol."},{"issue":"1","key":"2026091109072629800_cit28","doi-asserted-by":"publisher","first-page":"3","DOI":"10.1097\/JU.0000000000004723","article-title":"Updates to Recurrent Uncomplicated Urinary Tract Infections\nin Women: AUA\/CUA\/SUFU Guideline (2025)","volume":"215","author":"Ackerman","year":"2026","journal-title":"J.\nUrol."},{"issue":"12","key":"2026091109072629800_cit29","doi-asserted-by":"publisher","first-page":"2755","DOI":"10.1128\/JB.00105-13","article-title":"The Escherichia\nColi Cpx Envelope\nStress Response Regulates Genes of Diverse Function That Impact Antibiotic\nResistance and Membrane Integrity","volume":"195","author":"Raivio","year":"2013","journal-title":"J. Bacteriol."},{"issue":"9","key":"2026091109072629800_cit30","doi-asserted-by":"publisher","first-page":"1869","DOI":"10.1128\/JB.02197-12","article-title":"The Cpx Stress Response Confers Resistance to Some,\nbut Not All","volume":"195","author":"Mahoney","year":"2013","journal-title":"Bactericidal Antibiotics. J. Bacteriol."},{"issue":"4","key":"2026091109072629800_cit31","doi-asserted-by":"publisher","DOI":"10.1128\/IAI.00652","article-title":"Polymicrobial\nInteractions in the Urinary Tract: Is the Enemy of My Enemy My Friend?","volume":"89","author":"Gaston","year":"2021","journal-title":"Infect. Immun."},{"key":"2026091109072629800_cit32","author":"CLSI.","journal-title":"CLSI Micro Free"},{"key":"2026091109072629800_cit33","doi-asserted-by":"publisher","first-page":"59","DOI":"10.1007\/978-1-4939-0473-0_","article-title":"Plate-Based\nAssay for Swimming Motility in Pseudomonas Aeruginosa","volume-title":"Pseudomonas Methods and Protocols","author":"Ha","year":"2014"},{"key":"2026091109072629800_cit34","doi-asserted-by":"publisher","first-page":"2437","DOI":"10.3791\/2437","article-title":"Microtiter\nDish Biofilm Formation Assay","volume":"47","author":"O\u2019Toole","year":"2011","journal-title":"J. Visualized\nExp."},{"key":"2026091109072629800_cit35","doi-asserted-by":"publisher","DOI":"10.1016\/j.mex.2021.101543","article-title":"New and Simplified\nMethod for Drug Combination Studies by Checkerboard Assay","volume":"8","author":"Bellio","year":"2021","journal-title":"MethodsX"}],"container-title":["ACS Infectious Diseases"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/pubs.acs.org\/doi\/pdf\/10.1021\/acsinfecdis.6c00457","content-type":"application\/pdf","content-version":"vor","intended-application":"unspecified"},{"URL":"https:\/\/pubs.acs.org\/aidcbc\/article-pdf\/12\/9\/2995\/66972973\/acsinfecdis.6c00457.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"syndication"},{"URL":"https:\/\/pubs.acs.org\/aidcbc\/article-pdf\/12\/9\/2995\/66972973\/acsinfecdis.6c00457.pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,9,11]],"date-time":"2026-09-11T13:37:59Z","timestamp":1789133879000},"score":1,"resource":{"primary":{"URL":"https:\/\/pubs.acs.org\/aidcbc\/article\/12\/9\/2995\/5284518\/Phenotypic-Effects-of-a-Small-Molecule-CpxA"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,8,21]]},"references-count":35,"journal-issue":{"issue":"9","published-online":{"date-parts":[[2026,8,21]]},"published-print":{"date-parts":[[2026,9,11]]}},"URL":"https:\/\/doi.org\/10.1021\/acsinfecdis.6c00457","relation":{},"ISSN":["2373-8227"],"issn-type":[{"value":"2373-8227","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,8,21]]}}}