Rational design strategies for FimH antagonists: new drugs on the horizon for urinary tract infection and Crohn’s disease

ABSTRACT

Introduction: The bacterial adhesin FimH is a virulence factor and an attractive therapeutic target for urinary tract infection (UTI) and Crohn’s Disease (CD). Located on type 1 pili of uropathogenic E. coli (UPEC), the FimH adhesin plays an integral role in the pathogenesis of UPEC. Recent efforts have culminated in the development of small-molecule mannoside FimH antagonists that target the mannose-binding lectin domain of FimH, inhibiting its function and preventing UPEC from binding mannosylated host cells in the bladder, thereby circumventing infection.

Areas covered: The authors describe the structure-guided design of mannoside ligands, and review the structural biology of the FimH lectin domain. Additionally, they discuss the lead optimization of mannosides for therapeutic application in UTI and CD, and describe various assays used to measure mannoside potency in vitro and mouse models used to determine efficacy in vivo.

Expert opinion: To date, mannoside optimization has led to a diverse set of small-molecule FimH antagonists with oral bioavailability. With clinical trials already initiated in CD and on the horizon for UTI, it is the authors, opinion that mannosides will be a ‘first-in-class’ treatment strategy for UTI and CD, and will pave the way for treatment of other Gram-negative bacterial infections.

KEYWORDS:

• FimH
• mannoside
• lectin
• UTI
• Crohn’s disease
• UPEC
• pili
• bacterial adhesin
• AIEC
• structure-based drug design (SBDD)

Article highlights

• Anti-adhesive compounds called mannosides, which bind and inhibit the virulence factor FimH of uropathogenic E. coli (UPEC) and adherent invasive E. coli (AIEC) bacteria, have become a widely pursued alternative therapeutic strategy to antibiotics in urinary tract infection (UTI) and Crohn’s Disease (CD).

• Several diverse biochemical binding, biophysical and cell-based functional assays have been employed to measure FimH mannoside antagonist potency in vitro.

• Multiple in vivo mouse models have been developed to evaluate the efficacy of mannosides in acute and chronic UTI treatment and prevention as well as in CD.

• Understanding the structural biology of the FimH lectin domain and the key interactions of residues which participate in tight binding mainly to the aglycone portion of mannosides is critical to the design of potent FimH antagonists.

• X-ray structure-guided ligand design has been extensively utilized in the discovery and optimization of small molecule aryl mannoside FimH antagonists.

• Varied structural modifications to both the aryl aglycone and sugar portion of aryl mannosides have been employed in lead optimization of FimH mannosides resulting in the discovery of an extremely potent series of biaryl mannosides.

• Medicinal chemistry directed adjustments have resulted in the development of O-mannoside prodrugs and new C-mannosides with significantly improved efficacy and drug-like properties, including increased oral bioavailability and metabolic stability.

• Multimeric derivatives of mannosides with limited or no oral bioavailability have been pursued as drugs targeting AIEC in the gut. As a result, clinical candidate EB8018 was developed and entered Phase 1 trials in January of 2017 in CD patients.

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Declaration of interest

JW Janetka is a co-founder and stockholder of Fimbrion Therapeutics, Inc., and TJ Hannan and LK Mydock-McGrane are employees of Fimbrion who also hold company stock options. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.

Additional information

Funding

The authors are funded by a grant from the National Institute of Allergy and Infectious Disease via grant (no. 5R43A1106112-02).