The peptidoglycan endopeptidase MepH of uropathogenic Escherichia coli supports competitive fitness during prolonged urinary tract infections.

Urinary tract infections (UTIs) are predominantly caused by uropathogenic Escherichia coli (UPEC) and are characterized by frequent recurrence and persistence despite antibiotic treatment. Successful infection requires dynamic remodeling of the bacterial envelope to withstand host-derived stresses. Peptidoglycan endopeptidases mediate cell wall remodeling, yet the contribution of MepH to UPEC pathogenesis remains unclear. Here, we investigated the role of MepH using the prototypical UPEC strain UTI89. In a murine UTI model, deletion of mepH significantly reduced bacterial fitness in the urine at 2 days post-infection, as well as in the urine, bladder, and kidneys at 14 days post-infection. The mepH mutant exhibited impaired survival in mouse urine in a manner dependent on heat-labile components, decreased filamentous morphological switching in vivo, increased susceptibility to macrophage-mediated killing, and reduced resistance to detergent stress, while motility, epithelial cell association, serum resistance, and acid tolerance were unchanged. These findings identify MepH as a previously unrecognized virulence determinant that promotes prolonged UPEC infection, highlighting peptidoglycan remodeling enzymes as potential targets for anti-virulence strategies.