Antimicrobial Macrocycles - Synthesis, Characterization, and Activity Comparison with Their Linear Polycationic...

Area of Science:

• Medicinal Chemistry
• Antimicrobial Drug Discovery
• Polymer Chemistry

Background:

• Membrane-lytic compounds, including antimicrobial peptides (AMPs) and synthetic mimics (SMAMPs), are promising candidates for new antimicrobial agents.
• Despite nearly 30 years of research, SMAMPs face challenges hindering their clinical application.

Purpose of the Study:

• To investigate macrocyclic quaternary ammonium salts (MQAs) as a novel class of antimicrobial agents.
• To compare the antimicrobial activity and selectivity of MQAs with their known polymeric analogues (ionenes).

Main Methods:

• Redirected step-growth polymerization using a high dilution principle to synthesize MQAs from precursors of known antimicrobial ionenes.
• Antimicrobial assays and cytotoxicity studies to evaluate efficacy and safety.
• Membrane-lytic experiments using large unilamellar liposomes (LUVs) and whole cells to understand the mechanism of action.

Main Results:

• MQAs demonstrated high antimicrobial activity and superior selectivity compared to their polymeric ionene analogues.
• Significant differences were observed in the adsorption onto LUVs and microbial surfaces between MQAs and ionenes.
• Distinct differences in lipid bilayer permeabilization capabilities were noted between MQAs and ionenes.

Conclusions:

• Macrocyclic quaternary ammonium salts (MQAs) represent a new class of promising antibacterial agents with enhanced selectivity.
• MQAs exhibit distinct membrane-lytic properties compared to ionenes, suggesting a potentially improved mechanism of action for antimicrobial applications.