Centre for Drug Delivery Research, Faculty of Pharmacy, Universiti Kebangsaan Malaysia, Jalan Raja Muda Abdul Aziz, 50300 Kuala Lumpur, Malaysia.
Drug and Herbal Discovery Centre, Faculty of Pharmacy, Universiti Kebangsaan Malaysia, Jalan Raja Muda Abdul Aziz, 50300 Kuala Lumpur, Malaysia.
Carbohydr Polym. 2021 Feb 15;254:117299. doi: 10.1016/j.carbpol.2020.117299. Epub 2020 Oct 23.
Naturally derived antimicrobial peptides (AMPs) are an attractive source of new antimicrobial agents. However, clinical application of AMPs is associated with poor bioavailability and toxicity. In this study, we address these limitations by designing a new series of chitosan derivatives to mimic the amphiphilic topology of AMPs. The synthesized chitosan derivatives were found to self-assemble into nanoparticles in the aqueous environment. Among the compounds, a chitosan derivative grafted with arginine and oleic acid (CH-Arg-OA) exhibited the most potent antimicrobial activity, especially against Gram-negative bacteria. It also caused minimal cell death when tested in HEK293 and HepG2 cell lines, thus confirming the role of cationicity and lipophilicity for selective bacteria targeting. CH-Arg-OA exhibited its antimicrobial activity by disrupting bacterial membranes and causing the leakage of cytoplasmic contents. Thus, amphiphilic chitosan nanoparticles offer a great promise as a new class of AMPs mimics that is effective against Gram-negative bacteria.
天然抗菌肽 (AMPs) 是一种有吸引力的新型抗菌剂来源。然而，AMPs 的临床应用与较差的生物利用度和毒性有关。在这项研究中，我们通过设计一系列新的壳聚糖衍生物来模拟 AMPs 的两亲拓扑结构来解决这些限制。在水环境中，合成的壳聚糖衍生物被发现自组装成纳米粒子。在这些化合物中，接枝了精氨酸和油酸的壳聚糖衍生物 (CH-Arg-OA) 表现出最强的抗菌活性，特别是对革兰氏阴性菌。当在 HEK293 和 HepG2 细胞系中进行测试时，它引起的细胞死亡最小，从而证实了阳离子性和疏水性对选择性细菌靶向的作用。CH-Arg-OA 通过破坏细菌膜并导致细胞质内容物泄漏来发挥其抗菌活性。因此，两亲性壳聚糖纳米粒子作为一种有效的革兰氏阴性菌抗菌剂，很有希望成为一类新型的 AMP 模拟物。
