Targeting Force-Regulated FimH Adhesin: Assays, Mannosides, and Biologics for Anti-Virulence Therapy of UPEC Infection

Abstract Urinary tract infections (UTIs) are among the most common bacterial infections, and recurrent UTIs caused by uropathogenic Escherichia coli (UPEC) drive antibiotic use and antimicrobial resistance. FimH, the mannose-binding adhesin at the tip of type 1 pili, is a central UPEC virulence factor. Under shear force, FimH switches from a low-affinity, tense state to a high-affinity, relaxed state, strengthening adhesion during urine flow. This catch-bond behavior makes FimH a promising anti-virulence target, though a difficult one to drug. Here, we review strategies to target FimH, including monovalent and multivalent mannosides, vaccines, conformation-selective monoclonal antibodies, and de novo engineered miniproteins, together with the assays used to quantify FimH-ligand binding and UPEC adhesion. Clinical translation has been limited by assay-dependent potency, urinary pharmacokinetics, and intracellular reservoirs. We posit that effective FimH-targeted therapy requires alignment among inhibitor mechanism, FimH conformational state, bladder lumen exposure, and infection stage, which in turn defines realistic roles in prevention, early intervention, and combination therapy.