New Generation Antibiotics Derived from DABCO-Based Cationic Polymers

<b>Background/Objectives</b>: The growing threat of antibiotic resistance necessitates the development of novel antimicrobial agents that effectively target pathogenic microorganisms while minimizing toxicity. <b>Methods</b>: Two series DABCO-based cationic homopolymers (D-subs 1kDa, D-subs 5kDa, D-subs 15kDa) and DABCO-pyridinium-based copolymers (PyH-subs 5kDa_Dsubs 5kDa, PyH-subs 7kDa_Dsubs 3kDa, PyH-subs 3kDa_Dsubs 7kDa) were synthesized to mimic to host-defense cationic peptides via ring-opening metathesis polymerization (ROMP). The antimicrobial activities of these polymers were determined by their minimum inhibitory concentrations (MICs) against <i>E. coli</i> (Gram-negative bacteria), <i>P. aeruginosa</i> (Gram-negative bacteria), <i>S. aureus</i> (Gram-positive bacteria), and <i>C. albicans</i> (fungus). In vitro cytotoxicity assays revealed selective toxicity towards bacterial cells, with high selectivity indices for several copolymers. To gain insight into the mechanism of action, morphological changes in <i>S. aureus</i> upon exposure to D-subs 1kDa were examined using scanning electron microscopy (SEM) and transmission electron microscopy (TEM). <b>Results</b>: The D-subs 15kDa homopolymer demonstrated the highest overall antimicrobial activity, particularly against <i>S. aureus</i> (MIC: 8 µg/mL), with all polymers exhibiting minimal hemolytic activity (HC₅₀ ≥ 1024 µg/mL). SEM and TEM results revealed membrane disruption indicative of polymer-bacteria interactions. Additionally, stability studies confirmed polymer integrity under physiological conditions for at least 28 days. <b>Conclusions</b>: These results support the potential of DABCO-based cationic polymers as a promising platform for next-generation antimicrobial therapeutics.