Double agent: how Escherichia coli switches from commensal to pathogen in the urinary tract infection

Escherichia coli exhibits a dual nature as both a beneficial gut commensal and the predominant cause of community-acquired urinary tract infections (UTIs) worldwide. This review synthesizes current evidence establishing phenotypic plasticity the capacity for dynamic, non-heritable, and reversible adaptation as a central determinant of uropathogenic E. coli pathogenesis, distinct from stable genetic resistance. From a multilayered perspective, a comprehensive analysis is provided of how genomic diversity, host-pathogen interactions at the bladder epithelium, and exposure to clinically relevant antibiotics collectively drive morphological and regulatory reprogramming. These adaptations include surface roughening, filamentation, and RpoS-mediated persistence, along with (p)ppGpp stringent response and EnvZ/OmpR two-component system signaling, which enhance bacterial survival independently of genetic resistance mutations. The review further discusses how these mechanisms establish a coordinated survival matrix, creating a fundamental disconnect between standard antibiotic susceptibility testing and the host-associated phenotypes that characterize actual infections. Unlike genetically resistant bacteria that grow at elevated antibiotic concentrations, phenotypically tolerant cells exhibit normal MICs but require prolonged killing times, explaining why recurrent UTIs occur despite appropriate therapy. Finally, recent advances, including phage vB_EcoP_P64441 combined with cefotaxime for biofilm disruption, glucose-mediated gentamicin tolerance targeting metabolic pathways, and HDAC inhibitors such as valproic acid for host-directed epigenetic reprogramming, offer new opportunities to break the debilitating cycle of recurrent UTIs affecting millions worldwide.