Lysosomal activation in bladder epithelium enhances intracellular antibiotic clearance of uropathogenic Escherichia coli

Recurrent urinary tract infections (UTIs) are a major clinical burden, driven in part by the ability of uropathogenic Escherichia coli (UPEC) to establish intracellular niches within the bladder epithelium, where bacteria withstand antibiotics and host defenses. The oral bacterial lysate OM-89 (Uro-Vaxom(R)), 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-treatment regrowth in epithelial infection models. Using bladder organoids together with differentiated epithelial monolayers, OM-89 promotes lysosomal acidification and increases lysosomal protease activity, driving intracellular UPEC toward degradative compartments. In parallel, OM-89 improves intracellular antibiotic efficacy across multiple antibiotic classes, leading to enhanced bacterial clearance and reduced post-treatment bacterial recovery. These effects are conserved across distinct UPEC strains and in both murine and human epithelial models. Our findings position the bladder epithelium from a passive barrier to an active, targetable determinant of treatment outcome and suggest host-directed modulation of epithelial antimicrobial pathways as a promising strategy to enhance intracellular bacterial clearance.