β-Lactamase-activated antimicrobial dendron via the amine uncaging strategy

Area of Science:

• Medicinal Chemistry
• Antimicrobial Drug Development
• Nanotechnology

Background:

• Multidrug-resistant (MDR) bacteria pose a significant threat, necessitating novel antimicrobial strategies.
• Beta-lactamase enzymes produced by some bacteria confer resistance to common antibiotics.
• Cationic amphipathic molecules show antimicrobial potential but often suffer from toxicity and lack of specificity.

Purpose of the Study:

• To develop a novel membrane-active antimicrobial prodrug (BLM-Dendron) utilizing an amine uncaging strategy (AUS).
• To achieve targeted activation of antimicrobial agents specifically in the presence of beta-lactamase enzymes.
• To enhance the biocompatibility and reduce the cytotoxicity of cationic amphipathic antimicrobials.

Main Methods:

• Synthesis of BLM-Dendron, a prodrug based on AUS with masked amine groups.
• Characterization of BLM-Dendron self-assembly into nanoparticles (ca. 200 nm).
• Evaluation of antimicrobial activity against MDR bacteria (P. aeruginosa, E. coli, S. aureus) in the presence of penicillinase.
• Assessment of bactericidal and antibiofilm activities of the uncaged dendron.
• Mechanistic studies on membrane disruption.
• Evaluation of hemocompatibility and cytotoxicity.

Main Results:

• BLM-Dendron self-assembles into nanoparticles (ca. 200 nm in diameter).
• The prodrug exhibits bacteriostatic activity against MDR P. aeruginosa, E. coli, and S. aureus when beta-lactamase is present.
• The uncaged dendron demonstrates potent bactericidal activity (eliminating >99.99999% of planktonic cells) and antibiofilm effects against wild-type P. aeruginosa.
• Mechanistic studies confirm membrane disruption as the mode of action.
• BLM-Dendron shows significantly improved hemocompatibility and reduced cytotoxicity compared to the uncaged molecule.

Conclusions:

• The amine uncaging strategy (AUS) enables precise, enzyme-triggered activation of antimicrobial prodrugs.
• BLM-Dendron represents a promising new class of targeted antimicrobial agents with enhanced safety profiles.
• AUS is a valuable approach for developing clinically translatable antimicrobial therapies with improved biocompatibility and targeted activation.