Highly Effective, Water-Soluble, Hemocompatible 1,3-Propylene Oxide-Based Antimicrobials: Poly[(3,3-quaternary/PEG)-copolyoxetanes]

Abstract

This study focuses on the solution antimicrobial effectiveness of a novel class of copolyoxetanes with quaternary ammonium and PEG-like side chains. A precursor P[(BBOx-m)(ME2Ox)] copolyoxetane was prepared by cationic ring-opening copolymerization of 3-((4-bromobutoxy)methyl)-3-methyloxetane (BBOx) and 3-((2-(2-methoxyethoxy)ethoxy)methyl)-3-methyloxetane (ME2Ox) to give random copolymers with 14-100 (m) mol % BBOx. Reaction of P[(BBOx-m)(ME2Ox)] with dodecyl dimethylamine gave the corresponding quaternary P[(C12-m)(ME2Ox)] polycation salts, designated C12-m, as viscous liquids in 100% yield. BBOx/ME2Ox and C12/ME2Ox ratios were obtained by (1)H NMR spectroscopy. C12-m molecular weights (M(n), 3.5-21.9 kDa) were obtained from (1)H NMR end group analysis. DSC studies up to 150 °C showed only thermal transitions between -69 and -34 °C assigned to T(g) values. Antibacterial activity for the C12-m copolyoxetanes was tested by determining minimum inhibitory concentrations (MICs) against Gram(+) Staphylococcus aureus and Gram(-) Escherichia coli and Pseudomonas aeruginosa . MIC decreased with increasing C12 mol percent, reaching a minimum in the range C12-43 to C12-60. Overall, the antimicrobial with consistently low MICs for the three tested pathogenic bacteria was C12-43: (bacteria, MIC, μg/mL) E. coli (6), S. aureus (5), and P. aeruginosa (33). For C12-43, minimum biocidal concentration (MBC) to reach 99.99% kill in 24 h required 1.5× MIC for S. aureus and 2× MIC for E. coli and P. aeruginosa . At 5× MIC against a challenge of 10(8) cfu/mL, C12-43 kills ≥99% S. aureus , E. coli , and P. aeruginosa within 1 h. C12-m copolyoxetane cytotoxicity toward human red blood cells was low, indicating good prospects for biocompatibility. The tunability of C12-m copolyoxetane compositions, effective antimicrobial behavior against Gram(+) and Gram(-) bacteria, and promising biocompatibility offer opportunities for further modification and potential applications as therapeutic agents.

High Antimicrobial Effectiveness with Low Hemolytic and Cytotoxic Activity for PEG/Quaternary Copolyoxetanes

“…Using MICs as a metric, an optimum range for biocidal efficiency was 40–60 mol % C12. 1 To explore amphiphilic balance farther, the present study focuses on quaternary chain length keeping mol% quat constant. The compositions are designated C x -50, where x = 2, 6, 8, 10, 12, 14, and 16.…”

“…MICs for DTAB 1 are included for comparison with those previously reported by Seifert. 2 This comparison shows that MICs vary depending on bacterial strain and details of laboratory test procedures.…”

“…1 A higher ME2 monomer feed (55 mol % was used as BBOx is somewhat more reactive. For the designation P[(BBO x )(ME2Ox)-50:50-4], BBOx is the bromo-butoxymethyl side chain precursor to quat substitution, ME2Ox is the PEG-like side chain in 1 , 50:50 is the mole ratio of repeat units, and 4 is the approximate molecular weight in kDa based on 1 H NMR data and analyses are in Figure 1 and Supporting Information and GPC (Figure S3).…”

“…1 The quantities of the precursor and the respective tertiary amines used for quaternization are provided in Table 1. After removing solvent and excess amine in vacuo (liquid nitrogen trap), C x -50 copolyoxetanes were isolated as highly viscous liquids.…”

Controlling macromolecular structures towards effective antimicrobial polymers

“…Wynne and coworkers explored this phenomena on their copolyoxetanes with quaternary ammonium and PEG-like side chains [163]. Along with most polycations, the copolyoxetanes had a strong polyvalent effect compared with the monovalent analogs.…”