Smart Galactosidase-Responsive Antimicrobial Dendron: Towards More Biocompatible Membrane-Disruptive Agents

Area of Science:

• Medicinal Chemistry
• Biotechnology
• Drug Discovery

Background:

• Antimicrobial resistance (AMR) is a critical global health threat requiring novel therapeutic solutions.
• Antimicrobial peptides and their mimics show promise but often exhibit toxicity due to non-specific binding with host cells.
• Developing selective and less toxic antimicrobial agents remains a significant challenge.

Purpose of the Study:

• To synthesize a smart antimicrobial dendron with masked cationic groups (Gal-Dendron) that can be activated by β-galactosidase.
• To evaluate the antimicrobial activity and mechanism of the activated dendron (Enz-Dendron).
• To assess the toxicity profile of the masked prodrug compared to the activated form.

Main Methods:

• Synthesis of a dendron with masked cationic groups (Gal-Dendron).
• Enzymatic uncaging of the dendron using β-galactosidase to form the active Enz-Dendron.
• Antimicrobial activity testing against Gram-negative (P. aeruginosa, E. coli) and Gram-positive (S. aureus) bacteria.
• Minimum inhibitory concentration (MIC) determination.
• Membrane permeabilization assays (inner and outer membranes).
• Hemolysis assays and comparative toxicity studies.

Main Results:

• The activated Enz-Dendron demonstrated bacteriostatic activity against P. aeruginosa, E. coli, and S. aureus with MIC values of 96 µm.
• The antimicrobial mechanism involves disruption of bacterial membranes, evidenced by permeabilization assays.
• The masked prodrug Gal-Dendron exhibited significantly lower toxicity, showing at least 2.4 times less hemolysis compared to the activated Enz-Dendron.
• The responsive immolative linkers effectively masked cationic groups, improving selectivity and biocompatibility.

Conclusions:

• The smart dendron strategy successfully masked cationic groups, mitigating toxicity associated with antimicrobial peptides.
• Enzyme-triggered activation provides a targeted approach to deliver antimicrobial activity, enhancing safety.
• This study presents a promising platform for designing biocompatible, membrane-disruptive antimicrobial agents through amine uncaging strategies.