Institute of Bioengineering and Bioimaging, 31 Biopolis Way, The Nanos, Singapore, 138669, Singapore.
Adv Healthc Mater. 2022 Mar;11(6):e2101770. doi: 10.1002/adhm.202101770. Epub 2021 Dec 10.
Multidrug resistant infections are plaguing the healthcare sector over the past few decades with limited treatment options. To overcome this problem, the authors synthesize a series of novel guanidinium-functionalized polypeptides. Specifically, poly(l-lysine) (PLL) with different lengths is first synthesized by ring-opening polymerization of N -benzyloxycarbonyl-l-lysine-N-carboxyanhydride (Lys(Z)-NCA) followed by functionalization with a guanidinium-functional group to obtain guanidinium-functionalized PLL (PLL-Gua). To study the effect of hydrophobicity on antimicrobial activity, relatively more hydrophobic leucine-NCA monomer or hydrophobic vitamin E moiety is introduced to PLL-Gua. These polypeptides are characterized for antimicrobial activity against a panel of microbes including multidrug-resistant bacteria, and hemolytic activity. Among all the polypeptides, PLL -Gua is most effective against bacteria and yeast. Particularly, excellent bactericidal activity is observed against Staphylococcus aureus and MRSA. PLL -Gua kills bacteria mainly by membrane translocation. In addition, PLL -Gua kills MRSA with low resistance frequency (<3.3 × 10 ). In an MRSA-caused wound infection mouse model, two-day treatment (twice daily) with 10, 20, or 40 mg per kg of PLL -Gua shows up to 99.5% bacterial removal. Moreover, no acute dermal toxicity is observed even at a dose of 200 mg per kg. These promising results show the excellent potential of PLL -Gua as an antimicrobial agent against multidrug-resistant infection in vivo.
在过去的几十年里，多药耐药感染一直困扰着医疗保健行业，而治疗选择却非常有限。为了解决这个问题，作者合成了一系列新型胍基功能化多肽。具体来说，首先通过 N-苄氧羰基-l-赖氨酸-N-羧酸酐（Lys（Z）-NCA）的开环聚合合成不同长度的聚（l-赖氨酸）（PLL），然后用胍基官能团对其进行功能化，得到胍基功能化 PLL（PLL-Gua）。为了研究疏水性对抗菌活性的影响，相对更疏水的亮氨酸-NCA 单体或疏水性维生素 E 部分被引入 PLL-Gua。这些多肽的抗菌活性针对一系列微生物进行了研究，包括多药耐药菌和溶血活性。在所有多肽中，PLL-Gua 对细菌和酵母最有效。特别是，对金黄色葡萄球菌和耐甲氧西林金黄色葡萄球菌（MRSA）表现出极好的杀菌活性。PLL-Gua 主要通过膜转位杀死细菌。此外，PLL-Gua 以低耐药频率（<3.3×10-3）杀死 MRSA。在 MRSA 引起的伤口感染小鼠模型中，每天两次（每天两次）用 10、20 或 40mg/kg 的 PLL-Gua 治疗两天，可达到 99.5%的细菌清除率。此外，即使在 200mg/kg 的剂量下也没有观察到急性皮肤毒性。这些有前景的结果表明，PLL-Gua 作为一种抗多药耐药感染的抗菌剂，具有在体内应用的巨大潜力。
