State Key Laboratory of Bioreactor Engineering, East China University of Science and Technology, Shanghai 200237, China.
Key Laboratory for Ultrafine Materials of Ministry of Education, Frontiers Science Center for Materiobiology and Dynamic Chemistry, Shanghai Frontiers Science Center of Optogenetic Techniques for Cell Metabolism, Research Center for Biomedical Materials of Ministry of Education, School of Materials Science and Engineering, East China University of Science and Technology, Shanghai 200237, China.
J Am Chem Soc. 2022 Feb 2;144(4):1690-1699. doi: 10.1021/jacs.1c10659. Epub 2022 Jan 10.
Interest in developing antibacterial polymers as synthetic mimics of host defense peptides (HPDs) has accelerated in recent years to combat antibiotic-resistant bacterial infections. Positively charged moieties are critical in defining the antibacterial activity and eukaryotic toxicity of HDP mimics. Most examples have utilized primary amines or guanidines as the source of positively charged moieties, inspired by the lysine and arginine residues in HDPs. Here, we explore the impact of amine group variation (primary, secondary, or tertiary amine) on the antibacterial performance of HDP-mimicking β-peptide polymers. Our studies show that a secondary ammonium is superior to either a primary ammonium or a tertiary ammonium as the cationic moiety in antibacterial β-peptide polymers. The optimal polymer, a homopolymer bearing secondary amino groups, displays potent antibacterial activity and the highest selectivity (low hemolysis and cytotoxicity). The optimal polymer displays potent activity against antibiotic-resistant bacteria and high therapeutic efficacy in treating MRSA-induced wound infections and keratitis as well as low acute dermal toxicity and low corneal epithelial cytotoxicity. This work suggests that secondary amines may be broadly useful in the design of antibacterial polymers.
近年来，人们对开发具有抗菌作用的聚合物作为宿主防御肽 (HDP) 的人工模拟物的兴趣日益浓厚，以期对抗抗生素耐药性细菌感染。带正电荷的部分对于确定 HDP 模拟物的抗菌活性和真核毒性至关重要。大多数此类模拟物都利用伯胺或胍基作为带正电荷的部分的来源，这是受到 HDP 中赖氨酸和精氨酸残基的启发。在这里，我们研究了胺基变化（伯胺、仲胺或叔胺）对 HDP 模拟β-肽聚合物的抗菌性能的影响。我们的研究表明，在抗菌β-肽聚合物中，仲铵作为阳离子部分优于伯铵或叔铵。最优聚合物是含有仲氨基的均聚物，具有很强的抗菌活性和最高的选择性（溶血率和细胞毒性低）。最优聚合物对耐抗生素的细菌具有很强的活性，在治疗 MRSA 诱导的伤口感染和角膜炎方面具有很高的治疗效果，同时具有较低的急性皮肤毒性和较低的角膜上皮细胞毒性。这项工作表明，仲胺在抗菌聚合物的设计中可能具有广泛的用途。
