Key Laboratory of Infectious Immune and Antibody Engineering of Guizhou Province, Cellular Immunotherapy Engineering Research Center of Guizhou Province, School of Biology and Engineering/School of Basic Medical Sciences, Guizhou Medical University, Guiyang, China.
The Key and Characteristic Laboratory of Modern Pathogen Biology, Basic Medical College, Guizhou Medical University, Guiyang, China.
Microbiol Spectr. 2022 Dec 21;10(6):e0240922. doi: 10.1128/spectrum.02409-22. Epub 2022 Dec 1.
Staphylococcus epidermidis is part of the normal microbiota that colonizes the skin and mucosal surfaces of human beings. Previous studies suggested that S. epidermidis possessed low virulence, but recent studies confirmed that it can acquire high virulence from Staphylococcus aureus and with the increasing detection of methicillin-resistant S. epidermidis. It has become a major pathogen of graft-associated and hospital-acquired infections. In previous studies, we modified the antimicrobial peptide Cec4 (41 amino acids) and obtained the derived peptide C9 (16 amino acids) showing better antimicrobial activity against S. epidermidis with an MIC value of 8 μg/mL. The peptide has rapid bactericidal activity without detectable high-level resistance, showing certain inhibition and eradication ability on S. epidermidis biofilms. The damage of cell membrane structures by C9 was observed by scanning emission microscopy (SEM) and transmission electron microscopy (TEM). In addition, C9 altered the S. epidermidis cell membrane permeability, depolarization levels, fluidity, and reactive oxygen species (ROS) accumulation and possessed the ability to bind genomic DNA. Analysis of the transcriptional profiles of C9-treated cells revealed changes in genes involved in cell wall and ribosome biosynthesis, membrane protein transport, oxidative stress, and DNA transcription regulation. At the same time, the median lethal dose of C9 in mice was more than 128 mg/kg, and the intraperitoneal administration of 64 mg/kg was less toxic to the liver and kidneys of mice. Furthermore, C9 also showed a certain therapeutic effect on the mouse bacteremia model. In conclusion, C9 may be a candidate drug against S. epidermidis, which has the potential to be further developed as an antibacterial therapeutic agent. S. epidermidis is one of the most important pathogens of graft-related infection and hospital-acquired infection. The growing problem of antibiotic resistance, as well as the emergence of bacterial pathogenicity, highlights the need for antimicrobials with new modes of action. Antimicrobial peptides have been extensively studied over the past 30 years as ideal alternatives to antibiotics, and we report here that the derived peptide C9 is characterized by rapid bactericidal and antibiofilm activity, avoiding the development of resistance by acting on multiple nonspecific targets of the cell membrane or cell components. In addition, it has therapeutic potential against S. epidermidis infection . This study provides a rationale for the further development and application of C9 as an effective candidate antibiotic.
表皮葡萄球菌是定植于人类皮肤和黏膜表面的正常菌群的一部分。先前的研究表明，表皮葡萄球菌的毒力较低，但最近的研究证实，它可以从金黄色葡萄球菌获得高毒力，并且随着耐甲氧西林表皮葡萄球菌的检测增加，它已成为移植物相关和医院获得性感染的主要病原体。在之前的研究中，我们对抗菌肽 Cec4（41 个氨基酸）进行了修饰，得到了衍生肽 C9（16 个氨基酸），对表皮葡萄球菌的 MIC 值为 8μg/mL，表现出更好的抗菌活性。该肽具有快速杀菌活性，没有检测到高水平耐药性，对表皮葡萄球菌生物膜具有一定的抑制和清除能力。扫描发射显微镜（SEM）和透射电子显微镜（TEM）观察到 C9 对细胞膜结构的破坏。此外，C9 改变了表皮葡萄球菌细胞膜的通透性、去极化水平、流动性和活性氧（ROS）积累，并具有结合基因组 DNA 的能力。对 C9 处理细胞的转录谱分析显示，参与细胞壁和核糖体生物合成、膜蛋白转运、氧化应激和 DNA 转录调节的基因发生了变化。同时，C9 在小鼠中的半数致死量（LD50）大于 128mg/kg，腹腔内给予 64mg/kg 对小鼠的肝脏和肾脏毒性较小。此外，C9 对小鼠菌血症模型也表现出一定的治疗效果。综上所述，C9 可能是一种针对表皮葡萄球菌的候选药物，具有进一步开发为抗菌治疗药物的潜力。表皮葡萄球菌是移植物相关感染和医院获得性感染最重要的病原体之一。抗生素耐药性问题日益严重，以及细菌致病性的出现，突出表明需要具有新作用模式的抗菌药物。抗菌肽在过去 30 多年中得到了广泛研究，被认为是抗生素的理想替代品，我们在此报告衍生肽 C9 的特点是快速杀菌和抗生物膜活性，通过作用于细胞膜或细胞成分的多个非特异性靶标来避免耐药性的发展。此外，它对表皮葡萄球菌感染具有治疗潜力。这项研究为进一步开发和应用 C9 作为有效的候选抗生素提供了依据。
