Polytrimethylenimines: Highly Potent Antibacterial Agents with Activity and Toxicity Modulated by the Polymer Molecular Weight

• Published in: Biomacromolecules Vol. 24; no. 5; pp. 2237 - 2249
• Main Authors: Pachla, Julita, Kopiasz, Rafał J., Marek, Gabriela, Tomaszewski, Waldemar, Głogowska, Agnieszka, Drężek, Karolina, Kowalczyk, Sebastian, Podgórski, Rafał, Butruk-Raszeja, Beata, Ciach, Tomasz, Mierzejewska, Jolanta, Plichta, Andrzej, Augustynowicz-Kopeć, Ewa, Jańczewski, Dominik
• Format: Journal Article
• Language: English
• Published: United States American Chemical Society 08-05-2023
• Subjects: Anti-Bacterial Agents - pharmacology; Anti-Infective Agents; Gram-Negative Bacteria; Gram-Positive Bacteria; Microbial Sensitivity Tests; Molecular Weight; Polymers - pharmacology
• ISSN: 1525-7797; 1526-4602
• DOI: 10.1021/acs.biomac.3c00139

Cationic polymers have been extensively investigated as a potential replacement for traditional antibiotics. Here, we examined the effect of molecular weight (MW) on the antimicrobial, cytotoxic, and hemolytic activity of linear polytrimethylenimine (L-PTMI). The results indicate that the biological activity of the polymer sharply increases as MW increases. Thanks to a different position of the antibacterial activity and toxicity thresholds, tuning the MW of PTMI allows one to achieve a therapeutic window between antimicrobial activity and toxicity concentrations. L-PTMI presents significantly higher antimicrobial activity against model microorganisms than linear polyethylenimine (L-PEI) when polymers with a similar number of repeating units are compared. For the derivatives of L-PTMI and L-PEI, obtained through N-monomethylation and partial N,N-dimethylation of linear polyamines, the antimicrobial activity and toxicity were both reduced; however, resulting selectivity indices were higher. Selected materials were tested against clinical isolates of pathogens from the ESKAPE group and Mycobacteria, revealing good antibacterial properties of L-PTMI against antibiotic-resistant strains of Gram-positive and Gram-negative bacteria but limited antibacterial properties against Mycobacteria.