School of Pharmacy, Changzhou University, Changzhou 213164, China.
Department of Chemical and Biological Engineering, University of Sheffield, Sheffield S1 3JD, UK.
Biomater Sci. 2022 Aug 24;10(17):4848-4865. doi: 10.1039/d2bm00744d.
Antimicrobial peptides (AMPs) or host-defence peptides act by penetrating and disrupting the bacterial membranes and are therefore less prone to antimicrobial resistance (AMR) compared to conventional antibiotics. However, there are still many challenges in the clinical application of the naturally occurring AMPs which necessitates further studies to establish the relationship between the chemical structure of AMPs and their antimicrobial activity and selectivity. Herein, we report a study on the relationship between the chemical structure and the biological activity of a series of rationally designed AMPs derived from Ponericin-W1, a naturally occurring AMP from ants. The peptides were designed by modification of the hydrophobic and hydrophilic regions of the lead peptide sequence in a systematic way. Their antibacterial and hemolytic activities were determined . The antibacterial activity of a representative peptide, At5 was also tested in a mouse model of skin wound infection. Furthermore, the relationship between the physicochemical properties of the peptides and their antibacterial activity was investigated. Replacing the cationic amino acids in the hydrophobic region of the peptides with hydrophobic amino acids enhanced their antibacterial activity and increasing the number of cationic amino acids in the hydrophilic region reduced their toxicity to human red blood cells and thus improved their selectivity for bacteria. Four of the designed peptides, coded as At3, At5, At8, and At10, displayed considerable antibacterial activity and high selectivity for bacteria. At5 also accelerated the wound healing in mice indicating high efficiency of this peptide. The peptides were more effective against Gram-negative bacteria and no AMR was developed against them in the bacteria even after 25 generations. The results from this study can provide a better understanding of the structural features required for strong antibacterial activity and selectivity, and serve as a guide for the future rational design of AMPs.
抗菌肽（AMPs）或宿主防御肽通过穿透和破坏细菌膜起作用，因此与传统抗生素相比，不易产生抗菌耐药性（AMR）。然而，天然存在的 AMP 在临床应用中仍然存在许多挑战，这需要进一步的研究来建立 AMP 的化学结构与其抗菌活性和选择性之间的关系。在此，我们报告了一项关于一系列合理设计的 AMPs 的化学结构与生物学活性之间关系的研究，这些 AMPs 源自蚂蚁体内天然存在的 AMP 彭尼菌素-W1。这些肽是通过系统地修饰先导肽序列的疏水区和亲水区来设计的。测定了它们的抗菌和溶血活性。还在皮肤伤口感染的小鼠模型中测试了代表性肽 At5 的抗菌活性。此外，还研究了肽的理化性质与其抗菌活性之间的关系。用疏水性氨基酸取代肽的疏水区中的阳离子氨基酸增强了它们的抗菌活性，而增加亲水区中的阳离子氨基酸数量则降低了它们对人红细胞的毒性，从而提高了它们对细菌的选择性。设计的四种肽，编码为 At3、At5、At8 和 At10，显示出相当强的抗菌活性和对细菌的高选择性。At5 还加速了小鼠的伤口愈合，表明这种肽的效率很高。这些肽对革兰氏阴性菌更有效，并且即使在细菌中经过 25 代培养也没有对它们产生 AMR。这项研究的结果可以更好地了解产生强抗菌活性和选择性所需的结构特征，并为未来 AMP 的合理设计提供指导。
