Department of Biosciences and Bioengineering, Indian Institute of Technology Bombay, Mumbai 400076, India.
Department of Natural Products, National Institute of Pharmaceutical Education and Research (NIPER), Sector 67, S.A.S. Nagar, Mohali 160062, Punjab, India.
Int J Biol Macromol. 2024 Feb;259(Pt 2):129255. doi: 10.1016/j.ijbiomac.2024.129255. Epub 2024 Jan 8.
Several harmful bacteria have evolved resistance to conventional antibiotics due to their extensive usage. FtsZ, a principal bacterial cell division protein, is considered as an important drug target to combat resistance. We identified a caffeoyl anilide derivative, (E)-N-(4-(3-(3,4-dihydroxyphenyl)acryloyl)phenyl)-1-adamantylamide (compound 11) as a new antimicrobial agent targeting FtsZ. Compound 11 caused cell elongation in Mycobacterium smegmatis, Bacillus subtilis, and Escherichia coli cells, indicating that it inhibits cell partitioning. Compound 11 inhibited the assembly of Mycobacterium smegmatis FtsZ (MsFtsZ), forming short and thin filaments in vitro. Interestingly, the compound increased the rate of GTP hydrolysis of MsFtsZ. Compound 11 also impeded the assembly of Mycobacterium tuberculosis FtsZ. Fluorescence and absorption spectroscopic analysis suggested that compound 11 binds to MsFtsZ and produces conformational changes in FtsZ. The docking analysis indicated that the compound binds at the interdomain cleft of MsFtsZ. Further, it caused delocalization of the Z-ring in Mycobacterium smegmatis and Bacillus subtilis without affecting DNA segregation. Notably, compound 11 did not inhibit tubulin polymerization, the eukaryotic homolog of FtsZ, suggesting its specificity on bacteria. The evidence indicated that compound 11 exerts its antibacterial effect by impeding FtsZ assembly and has the potential to be developed as a broad-spectrum antimicrobial agent.
由于广泛使用，几种有害细菌已经对传统抗生素产生了耐药性。FtsZ，一种主要的细菌细胞分裂蛋白，被认为是对抗耐药性的重要药物靶点。我们鉴定出一种咖啡酰苯胺衍生物，（E）-N-（4-（3-（3,4-二羟基苯基）丙烯酰基）苯基）-1-金刚烷基酰胺（化合物 11），作为一种针对 FtsZ 的新型抗菌剂。化合物 11 导致分枝杆菌、枯草芽孢杆菌和大肠杆菌细胞伸长，表明它抑制细胞分裂。化合物 11 抑制分枝杆菌 FtsZ（MsFtsZ）的组装，在体外形成短而细的丝。有趣的是，该化合物增加了 MsFtsZ 的 GTP 水解速率。化合物 11 还阻碍了结核分枝杆菌 FtsZ 的组装。荧光和吸收光谱分析表明，化合物 11 与 MsFtsZ 结合并导致 FtsZ 构象发生变化。对接分析表明，该化合物结合在 MsFtsZ 的结构域裂缝中。此外，它导致分枝杆菌和枯草芽孢杆菌中的 Z 环定位，而不影响 DNA 分离。值得注意的是，化合物 11 不抑制微管蛋白聚合，即 FtsZ 的真核同源物，表明其对细菌具有特异性。这些证据表明，化合物 11 通过阻碍 FtsZ 组装发挥其抗菌作用，并有可能开发为一种广谱抗菌剂。
