Molecular Biophysics Unit (MBU), Indian Institute of Science, Bangalore, India.
Department of Microbiology and Cell Biology, Indian Institute of Science, Bangalore, India.
EMBO Rep. 2023 Jul 5;24(7):e55338. doi: 10.15252/embr.202255338. Epub 2023 May 11.
The bacterial toxin CcdB (Controller of Cell death or division B) targets DNA Gyrase, an essential bacterial topoisomerase, which is also the molecular target for fluoroquinolones. Here, we present a short cell-penetrating 24-mer peptide, CP1-WT, derived from the Gyrase-binding region of CcdB and examine its effect on growth of Escherichia coli, Salmonella Typhimurium, Staphylococcus aureus and a carbapenem- and tigecycline-resistant strain of Acinetobacter baumannii in both axenic cultures and mouse models of infection. The CP1-WT peptide shows significant improvement over ciprofloxacin in terms of its in vivo therapeutic efficacy in treating established infections of S. Typhimurium, S. aureus and A. baumannii. The molecular mechanism likely involves inhibition of Gyrase or Topoisomerase IV, depending on the strain used. The study validates the CcdB binding site on bacterial DNA Gyrase as a viable and alternative target to the fluoroquinolone binding site.
细菌毒素 CcdB（细胞死亡或分裂控制器 B）靶向 DNA 拓扑异构酶 Gyrase，这是一种必需的细菌拓扑异构酶，也是氟喹诺酮类药物的分子靶标。在这里，我们提出了一种短的细胞穿透 24 肽 CP1-WT，它来源于 CcdB 的 Gyrase 结合区域，并研究了它对大肠杆菌、鼠伤寒沙门氏菌、金黄色葡萄球菌和碳青霉烯类和替加环素耐药的鲍曼不动杆菌在无菌培养和感染小鼠模型中的生长的影响。CP1-WT 肽在治疗鼠伤寒沙门氏菌、金黄色葡萄球菌和鲍曼不动杆菌已建立感染方面的体内治疗效果明显优于环丙沙星。其分子机制可能涉及抑制 Gyrase 或拓扑异构酶 IV，具体取决于所用菌株。该研究验证了细菌 DNA 拓扑异构酶 Gyrase 上的 CcdB 结合位点是一种可行的、替代氟喹诺酮结合位点的替代靶标。
