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The oral bacterial lysate OM-89 (Uro-Vaxom), a clinically approved and globally used therapy for the prevention and management of recurrent UTIs for several decades, reduces recurrence rates, but its cellular mechanisms of action remain incompletely understood. Here, we demonstrate that OM-89 strengthens antimicrobial defenses in bladder epithelial cells and, in combination with antibiotic therapy, limits post-antibiotic bacterial regrowth in epithelial infection models. OM-89 promotes lysosomal acidification and increases lysosomal protease activity in bladder organoids and differentiated epithelial monolayers, thereby directing intracellular UPEC toward degradative compartments. In parallel, OM-89 enhances intracellular accumulation of multiple antibiotic classes. These effects are conserved across distinct UPEC strains and in both murine and human epithelial models. Our findings demonstrate that bladder epithelial antimicrobial pathways can be pharmacologically reinforced to influence treatment outcomes by enhancing intracellular bacterial clearance.<\/jats:p>","DOI":"10.1371\/journal.ppat.1014448","type":"journal-article","created":{"date-parts":[[2026,9,25]],"date-time":"2026-09-25T17:24:06Z","timestamp":1790357046000},"page":"e1014448","update-policy":"https:\/\/doi.org\/10.1371\/journal.ppat.corrections_policy","source":"Crossref","is-referenced-by-count":1,"title":["Targeted lysosomal activation in bladder epithelium enhances clearance of intracellular uropathogenic Escherichia coli"],"prefix":"10.1371","volume":"22","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-3768-877X","authenticated-orcid":true,"given":"Kathrin","family":"Tomasek","sequence":"first","affiliation":[{"name":"Laboratory of Microbiology and Microtechnology, School of Life Sciences (SV), \u00c9cole Polytechnique F\u00e9d\u00e9rale de Lausanne","place":["Lausanne, 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