Du Ruo-Lan, Hung Cheung-Hin, Leung Alan Siu-Lun, Ding Kang, Kong Wai-Po, Wang Yong, Liang Zhi-Guang, Chan Pak-Ho, Wong Kwok-Yin
Department of Applied Biology and Chemical Technology (ABCT), The Hong Kong Polytechnic University, Hung Hom, Kowloon, Hong Kong.
ACS Infect Dis. 2025 Aug 8;11(8):2190-2204. doi: 10.1021/acsinfecdis.5c00220. Epub 2025 Jul 24.
The rapid increase in bacterial resistance to conventional antibiotics has led to a great demand for novel antibacterial agents. Antimicrobial peptides (AMPs) are emerging as next-generation antimicrobial alternative drugs to conventional antibiotics because of their broad-spectrum antimicrobial activities and minimal potential for drug resistance induction. This work describes novel antimicrobial peptides (FtsZpcpp) synthesized through the conjugation of a cell penetration peptide ((RXR)XB) to nonantimicrobial peptides (FtsZp). The FtsZp peptides were previously identified to bind FtsZ (flaming-temperature-sensitive protein Z), a crucial protein in regulating bacterial cell divisions. Newly designed FtsZpcpp peptides have broad antimicrobial activities against both Gram-positive and Gram-negative bacteria, including multidrug-resistant strains. Besides, these new peptides exert minimal hemolytic activity toward human red blood cells and low cytotoxicity toward human skin cells. Comprehensive studies on the antimicrobial mechanism of FtsZpcpp peptides revealed that they exert antimicrobial activities through multiple mechanisms, including membrane disruption and intracellular actions (e.g., interference with cell divisions, DNA binding, and reactive oxygen species (ROS) generation). Our results have shown that FtsZpcpp peptides have the potential to serve as future antimicrobial drugs in combating the increasing global problem of antibiotic resistance.
细菌对传统抗生素的耐药性迅速增加，导致对新型抗菌剂的巨大需求。抗菌肽（AMPs）因其广谱抗菌活性和诱导耐药性的可能性极小，正作为传统抗生素的下一代抗菌替代药物而兴起。这项工作描述了通过将细胞穿透肽（(RXR)XB）与非抗菌肽（FtsZp）偶联而合成的新型抗菌肽（FtsZpcpp）。FtsZp肽先前被鉴定为可结合FtsZ（火焰温度敏感蛋白Z），这是一种调节细菌细胞分裂的关键蛋白。新设计的FtsZpcpp肽对革兰氏阳性菌和革兰氏阴性菌均具有广泛的抗菌活性，包括多重耐药菌株。此外，这些新肽对人类红细胞的溶血活性极小，对人类皮肤细胞的细胞毒性较低。对FtsZpcpp肽抗菌机制的综合研究表明，它们通过多种机制发挥抗菌活性，包括膜破坏和细胞内作用（如干扰细胞分裂、DNA结合和活性氧（ROS）生成）。我们的结果表明，FtsZpcpp肽有潜力作为未来的抗菌药物，以应对日益严重的全球抗生素耐药性问题。
