Novel Lectin-Targeting therapeutics and diagnostics for Pseudomonas aeruginosa infections

Reference Number TO 02-00396

Keywords

P. aeruginosa, biofilms, LecA inhibitors, LecB inhibitors, prodrug antibiotic conjugates, cystic fibrosis

Invention Novelty

Three distinct approaches targeting bacterial lectins LecA and LecB, critical components in the biofilm formation of Pseudomonas aeruginosa, to prevent nosocomial and chronic infections, in cystic fibrosis and immunocompromised patients:

Lectin-targeting conjugates: Prodrug antibiotic and imaging agent conjugates designed to bind bacterial lectins, utilizing bacterial proteases for selective drug release at infection sites
Bivalent LecA inhibitors: Glycomimetic inhibitors that prevent bacterial virulence and biofilm formation by blocking LecA, enhancing bacterial vulnerability to antibiotic treatment and the immune system
LecB inhibitors: Small molecules that disrupt biofilms and sensitize bacteria to antibiotics

Value Proposition

Targeted therapy: Direct drugs to infection sites, reducing systemic side effects
Enhanced antibiotic efficacy: Disrupts biofilm integrity, making bacteria more susceptible to treatment
Improved pharmacokinetics: Increased stability, solubility, and targeted action
Versatile application: Potential as a stand-alone or adjunctive therapeutic and as a diagnostic probe
These features highlight the potential to meet an unmet medical need in P. aeruginosa treatment.

Diagnostic approach using the antibiotic prodrug (modified from Zahorska et al. and Meiers et al.)

Technology Description

In vitro activity: Nanomolar binding affinity, inhibition of bacterial virulence and biofilm formation
In vitro ADME/T: Excellent profile with low cytotoxicity
In vivo target engagement: Synergy with tobramycin in chronic P. aeruginosa murine lung infection model
In vivo PK: High oral bioavailability, good plasma exposure, urinary excretion, high dose of 150 mg/kg/d without signs of toxicity

Commercial Opportunity

The technology is available for co-development and in-licensing partnerships.

Development Status

In vivo proof-of-concept for frontrunners of LecB inhibition in chronic lung infection model, LecA inhibitors effective in vitro, LecA/LecB targeting demonstrated in murine infection model.

Patent Situation

Three patent families (WO2016151066, WO2021089729, WO2023104922) with granted patents in EU, US, JP, CN, AU, IL and a pending application in CA. Additional pending applications exist in EP, US, JP, CA, AU, IL, and CN.