Dual Function Antimicrobial Loaded Lectin Carrier: A Strategy to Overcome Biomolecular Interference without...

Area of Science:

• Biochemistry and Molecular Biology
• Antimicrobial Drug Development
• Nanotechnology in Medicine

Background:

• Drug disposition is affected by biological fluids, with protein binding impacting activity.
• Cationic N-acylethanolamine (cNAE) antimicrobial activity is hindered by serum protein interference.
• Butea monosperma seed lectin (BMSL) can be formulated to mitigate such interferences.

Purpose of the Study:

• To develop a noncovalent formulation of BMSL and cNAE (BcNAE) to overcome serum protein interference.
• To evaluate the antimicrobial efficacy and resistance potential of BcNAE against uropathogenic Escherichia coli (UPEC).
• To assess the biosafety and therapeutic potential of BcNAE in preclinical models.

Main Methods:

• Noncovalent formulation of BMSL and cNAE.
• Fluorescence spectroscopy and molecular docking to study complex formation.
• Minimum inhibitory concentration (MIC) assays, membrane depolarization studies, resistance development assays.
• Hemocompatibility tests, zebrafish infection model for efficacy and biosafety assessment.

Main Results:

• BcNAE conjugates effectively mitigated serum protein interference, showing a 4-fold lower MIC (7.81 μM) than pure cNAE against UPEC.
• BcNAE demonstrated potent antimicrobial activity by depolarizing bacterial membranes and preventing resistance development even after 25 passages.
• Zebrafish studies confirmed BcNAE's efficacy, safety, and rapid clearance of UPEC infection with restored tissue pathology and increased survival.

Conclusions:

• Lectin-lipid conjugates (BcNAE) offer a novel strategy to enhance antimicrobial efficacy by overcoming biological fluid interference.
• BcNAE exhibits potent, membrane-targeting antimicrobial activity with a low propensity for resistance development and good biosafety.
• BcNAE represents a promising candidate for developing new therapeutics against challenging bacterial infections.