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Here, we investigate the previously uncharacterized gene\n                    <jats:italic>PA3049<\/jats:italic>\n                    , which is upregulated under biofilm conditions, to determine its role in infection, biofilm formation, and antimicrobial sensitivity. We show that the small uncharacterised protein PA3049, renamed as\n                    <jats:italic>B<\/jats:italic>\n                    iofilm\n                    <jats:italic>a<\/jats:italic>\n                    rchi\n                    <jats:italic>t<\/jats:italic>\n                    ecture\n                    <jats:italic>R<\/jats:italic>\n                    egulator (BatR), promotes biofilm establishment and enhances biofilm survival in sub-inhibitory concentrations of antibiotics. Proteomic analysis revealed that BatR influences the R2\/F2 pyocin cluster, which drives explosive cell lysis and extracellular DNA (eDNA) release during biofilm development. We further identify a specific interaction between BatR and PA0486 (SrkA), an uncharacterised Ser\/Thr protein kinase. We show that SrkA controls biofilm and pyocyanin production, and lysis-mediated eDNA release through regulation of the R2\/F2 pyocin cluster and activation of bacteriophage Pf4. Our findings support a model in which SrkA directly regulates key biofilm-associated phenotypes, while BatR acts as a modulatory partner that tunes SrkA activity under specific conditions. Finally, BatR function was tested in high-validity infection models, including the\n                    <jats:italic>ex vivo<\/jats:italic>\n                    pig lung model of cystic fibrosis infection and a synthetic chronic-wound model. In these models, BatR contributes to biofilm architecture and antibiotic resistance and modulates pyocyanin production. Our study implicates the BatR\/SrkA system in the response of\n                    <jats:italic>P. aeruginosa<\/jats:italic>\n                    biofilms to antibiotic challenge in lung infections.\n                  <\/jats:p>","DOI":"10.1371\/journal.ppat.1013832","type":"journal-article","created":{"date-parts":[[2026,7,28]],"date-time":"2026-07-28T17:25:33Z","timestamp":1785259533000},"page":"e1013832","update-policy":"https:\/\/doi.org\/10.1371\/journal.ppat.corrections_policy","source":"Crossref","is-referenced-by-count":1,"title":["A novel stress response pathway mediates biofilm architecture in Pseudomonas aeruginosa"],"prefix":"10.1371","volume":"22","author":[{"given":"Ainelen","family":"Piazza","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Catriona M. A.","family":"Thompson","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Govind","family":"Chandra","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Harshanie","family":"Dasanayaka","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Gerhard","family":"Saalbach","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Carlo","family":"Martins","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Eleftheria","family":"Trampari","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mark A.","family":"Webber","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Freya","family":"Harrison","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1959-6820","authenticated-orcid":true,"given":"Jacob G.","family":"Malone","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"340","published-online":{"date-parts":[[2026,7,28]]},"reference":[{"issue":"8","key":"ppat.1013832.ref001","doi-asserted-by":"crossref","first-page":"1079","DOI":"10.1086\/533452","article-title":"Federal funding for the study of antimicrobial resistance in nosocomial pathogens: no ESKAPE","volume":"197","author":"LB Rice","year":"2008","journal-title":"J Infect Dis"},{"issue":"5","key":"ppat.1013832.ref002","doi-asserted-by":"crossref","first-page":"538","DOI":"10.1111\/j.1442-2042.2006.01359.x","article-title":"Complicated 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