Methacrylamide based antibiotic polymers with no detectable bacterial resistance.

Area of Science:

• Polymer Chemistry
• Antimicrobial Agents
• Drug Discovery

Background:

• Rising threat of multidrug-resistant pathogens necessitates novel therapeutic strategies.
• Synthetic mimics of antimicrobial peptides (SMAMPs) are emerging as promising antibiotic alternatives.
• Antimicrobial polymers offer tunable properties for enhanced efficacy and reduced toxicity.

Purpose of the Study:

• To synthesize and evaluate novel amphiphilic, water-soluble cationic copolymers as potential antimicrobial agents.
• To investigate the structure-activity relationship of these polymers against bacterial pathogens.
• To assess the mechanism of action and potential for resistance development.

Main Methods:

• Synthesis of 7 copolymers based on aminopropyl methacrylamide and benzyl methacrylamide.
• Broth microdilution assay for antibacterial activity against Staphylococcus aureus and Escherichia coli.
• Hemolysis assay using human red blood cells to determine mammalian cell toxicity.
• Liposome dye leakage, confocal, and scanning electron microscopy to elucidate the mechanism of action.
• Serial passage study to assess resistance development.

Main Results:

• Copolymers demonstrated significant antibacterial activity, with efficacy dependent on benzyl content (f_benzyl) and molecular weight (M_n).
• Polymers AB-10 (f_benzyl=0.10) and AB-19 (f_benzyl=0.19) showed highest efficacy and selectivity, with no observed hemolysis.
• Mechanism of action involves disruption of the bacterial cytoplasmic membrane.
• No resistant mutants of E. coli or S. aureus were developed against AB-19 after 30 days of serial passage.

Conclusions:

• Amphiphilic cationic copolymers are effective antimicrobial agents against S. aureus and E. coli.
• AB-10 and AB-19 exhibit potent antibacterial activity and low mammalian cell toxicity.
• These polymers represent a promising new class of antimicrobials with a low propensity for resistance development.