Uropathogenic Escherichia coli in Recurrent Urinary Tract Infection: Intracellular Persistence, Immune Evasion, Antimicrobial Resistance, and Non-Antibiotic Interventions.

Uropathogenic Escherichia coli (UPEC) remains the principal driver of urinary tract infections (UTIs), utilizing sophisticated immunoevasive strategies that consistently outmaneuver host defenses and conventional clinical management. This review synthesizes current evidence highlighting the development of recurrent UTIs (rUTIs). Particular emphasis is given to the transition of UPEC into intracellular bacterial communities (IBCs) and quiescent intracellular reservoirs (QIRs)-survival phenomena primarily characterized across specialized mammalian and cellular models. By highlighting the translational evidence gaps surrounding these intracellular sanctuaries, and the challenge of directly extrapolating these model-derived dynamics to human recurrent UTIs (rUTIs), alongside the role of extra-urinary niches, we provide a comprehensive view of the mechanisms driving recurrence. A critical assessment of the UPEC virulence arsenal, involving molecular mechanisms that regulate fimbrial phase variation resulting in evading host immune surveillance, to specialized adhesins, like FimH, which tightly bind uroplakin receptors, triggering host actin rearrangements via rho-GTPase signaling and facilitating bacterial internalization, is also addressed. Additionally, we integrate the roles of cytotoxic necrotizing factor-1 (CNF1) and hemolysin A (HlyA) in promoting cytosolic escape, host cell survival, and long-term persistence. Finally, this review presents a multidisciplinary framework evaluating next-generation non-antibiotic strategies, including bacteriophage therapy, vaccines, phytotherapy, probiotics, and estrogen therapy. By critically assessing their efficacy and clinical maturity across a spectrum of preclinical models and human trials, we evaluate the potential to navigate translational limitations to effectively disrupt the infection cycle.