Anti-Adhesion Therapy: A New Frontier Against Bacterial Infections

Feb 8, 2026 · 11 min read · Microbiology, Drug Development

As antimicrobial resistance (AMR) continues its relentless rise, with the WHO estimating that drug-resistant infections caused 1.27 million deaths globally in 2019, the need for alternative therapeutic strategies has become critical. Anti-adhesion therapy -- which prevents bacterial attachment to host tissues rather than killing bacteria directly -- represents a promising approach that could complement or replace conventional antibiotics while potentially avoiding resistance development.

The Rationale for Anti-Adhesion Strategies

Bacterial adhesion to host tissues is the critical first step in the infectious process. Without successful attachment, bacteria are cleared by mechanical forces (urine flow, mucociliary clearance, peristalsis) and innate immune defenses. Anti-adhesion compounds offer several theoretical advantages:

FimH Antagonists: The Most Advanced Anti-Adhesion Approach

The FimH adhesin of type 1 fimbriae in uropathogenic E. coli (UPEC) is the most extensively studied target for anti-adhesion therapy. FimH binds to mannose residues on uroplakin receptors of the bladder epithelium, enabling colonization and invasion of umbrella cells.

Key Advance: Mannosides designed by Hultgren, Janetka, and colleagues (Washington University) are orally bioavailable FimH antagonists that bind the FimH lectin domain with nanomolar affinity. In preclinical models, these compounds reduced bladder bacterial titers by >10,000-fold and were effective against multidrug-resistant UPEC strains, including those resistant to all first-line antibiotics (Cusumano et al., 2011; Spaulding et al., 2017).

The optimized mannoside GS-9826 (now in clinical development) demonstrated several remarkable properties: oral bioavailability, efficacy as both prophylaxis and treatment, activity against intracellular bacterial communities (IBCs) that harbor persister cells, and potentiation of antibiotic activity when used in combination.

Reference: Spaulding CN, Klein RD, Ruer S, et al. Selective depletion of uropathogenic E. coli from the gut by a FimH antagonist. Nature. 2017;546(7659):528-532. doi:10.1038/nature22972

Pilicides and Curlicides

Pilicides are small molecules that inhibit the chaperone-usher pathway required for pilus assembly in Gram-negative bacteria. By blocking FimC (the chaperone) or FimD (the outer membrane usher), pilicides prevent fimbrial biogenesis and thus adhesion. Ring-fused 2-pyridones developed by Almqvist and colleagues have shown efficacy against UPEC biofilm formation in vitro.

Curlicides target the curli biogenesis pathway, preventing amyloid fiber formation. Since curli are major components of the biofilm matrix, curlicides can disrupt biofilm architecture and enhance antibiotic penetration.

Anti-Biofilm Strategies

Reference: Flores-Mireles AL, Walker JN, Caparon M, Hultgren SJ. Urinary tract infections: epidemiology, mechanisms of infection and treatment options. Nat Rev Microbiol. 2015;13(5):269-284. doi:10.1038/nrmicro3432
Disclaimer: This article is for educational purposes only. Anti-adhesion therapies described are investigational and not yet approved for clinical use. Always follow evidence-based treatment guidelines for bacterial infections.