Department of Chemistry, Texas A&M University, College Station, TX 77843.
Department of Chemical Engineering, University of Massachusetts, Amherst, MA 01003.
Proc Natl Acad Sci U S A. 2023 Dec 19;120(51):e2311396120. doi: 10.1073/pnas.2311396120. Epub 2023 Dec 11.
Cationic polymers have been identified as a promising type of antibacterial molecules, whose bioactivity can be tuned through structural modulation. Recent studies suggest that the placement of the cationic groups close to the core of the polymeric architecture rather than on appended side chains might improve both their bioactivity and selectivity for bacterial cells over mammalian cells. However, antibacterial main-chain cationic polymers are typically synthesized via polycondensations, which do not afford precise and uniform molecular design. Therefore, accessing main-chain cationic polymers with high degrees of molecular tunability hinges upon the development of controlled polymerizations tolerating cationic motifs (or cation progenitors) near the propagating species. Herein, we report the synthesis and ring-opening metathesis polymerization (ROMP) of -methylpyridinium-fused norbornene monomers. The identification of reaction conditions leading to a well-controlled ROMP enabled structural diversification of the main-chain cationic polymers and a study of their bioactivity. This family of polyelectrolytes was found to be active against both Gram-negative () and Gram-positive (Methicillin-resistant ) bacteria with minimal inhibitory concentrations as low as 25 µg/mL. Additionally, the molar mass of the polymers was found to impact their hemolytic activity with cationic polymers of smaller degrees of polymerization showing increased selectivity for bacteria over human red blood cells.
阳离子聚合物已被确定为一种很有前途的抗菌分子类型，其生物活性可以通过结构调节来进行调控。最近的研究表明，将阳离子基团置于聚合物结构的核心附近，而不是在侧链上附加，可能会提高它们对细菌细胞而非哺乳动物细胞的生物活性和选择性。然而，抗菌主链阳离子聚合物通常通过缩聚反应合成，这种方法无法实现精确和均匀的分子设计。因此，开发能够容忍靠近聚合物种的阳离子结构单元（或阳离子前体）的可控聚合反应，是获得具有高度分子可调性的主链阳离子聚合物的关键。在此，我们报告了 - 甲基吡啶鎓稠合降冰片烯单体的合成和开环复分解聚合（ROMP）。确定导致良好控制的 ROMP 的反应条件，使主链阳离子聚合物的结构多样化，并研究其生物活性。发现该系列聚电解质对革兰氏阴性（）和革兰氏阳性（耐甲氧西林）细菌均具有活性，最低抑菌浓度低至 25 µg/mL。此外，聚合物的摩尔质量对其溶血活性有影响，低聚合度的阳离子聚合物对细菌的选择性高于人红细胞。
