State Key Laboratory of Chemical Biology and Drug Discovery and Department of Applied Biology and Chemical Technology, The Hong Kong Polytechnic University, Hung Hom, Kowloon, Hong Kong SAR, China.
Shenzhen Key Laboratory for Food Biological Safety Control, Food Safety and Technology Research Centre, The Hong Kong Polytechnic University Shenzhen Research Institute, Shenzhen, China.
ChemMedChem. 2019 Aug 20;14(16):1547-1559. doi: 10.1002/cmdc.201900364. Epub 2019 Jul 30.
Phenol-soluble modulins (PSMs) are a large family of cytolytic peptide toxins produced by Staphylococcus aureus. Based on their amino acid sequences, we have constructed a small library of cationic isoleucine-rich peptides for antimicrobial evaluation. Relative to the parent PSMs, peptide zp3 (GIIAGIIIKIKK-NH ) was found to possess greatly improved physicochemical properties (soluble in water) and antibacterial activity (MIC=8 μm for E. coli, B. subtilis, and C. freundii) while maintaining low hemolytic activity (<5 % at 256 μm) and cytotoxicity (HEK293 cells IC >80 μm). We reasoned that the selective activity of zp3 toward bacterial cells is due to its amphiphilic nature and positive net charge. Moreover, it is difficult for bacteria to develop resistance against zp3. Through microscopic studies of E. coli, we demonstrated that zp3 can penetrate the bacterial membrane, thereby causing leakage of the bacterial cytoplasm. Our findings present a promising antimicrobial peptide lead, which has great potential for further chemical modification.
酚溶性调节素（PSMs）是由金黄色葡萄球菌产生的一大类细胞溶解肽毒素。基于它们的氨基酸序列，我们构建了一个阳离子性富含异亮氨酸的小肽文库，用于抗菌评估。与亲本 PSMs 相比，肽 zp3（GIIAGIIIKIKK-NH ）具有大大改善的物理化学性质（可溶于水）和抗菌活性（MIC=8μm 对大肠杆菌、枯草芽孢杆菌和弗氏柠檬酸杆菌），同时保持低溶血活性（<5% 在 256μm 时）和细胞毒性（HEK293 细胞 IC >80μm）。我们推断，zp3 对细菌细胞的选择性活性是由于其两亲性和正净电荷。此外，细菌很难对 zp3 产生耐药性。通过对大肠杆菌的显微镜研究，我们证明 zp3 可以穿透细菌膜，从而导致细菌细胞质泄漏。我们的研究结果提供了一种很有前途的抗菌肽先导物，具有进一步化学修饰的巨大潜力。
