Department of Biosciences and Biomedical Engineering, Indian Institute of Technology Indore, Simrol, Indore 453552, India.
Department of Medical Biotechnology, Gujarat Biotechnology University, Gandhinagar 382355, India.
Int J Biol Macromol. 2024 Jun;269(Pt 1):131806. doi: 10.1016/j.ijbiomac.2024.131806. Epub 2024 Apr 25.
Acinetobacter baumannii is a notorious pathogen that commonly thrives in hospital environments and is responsible for numerous nosocomial infections in humans. The burgeoning multi-drug resistance leaves relatively minimal options for treating the bacterial infection, posing a significant problem and prompting the identification of new approaches for tackling the same. This motivated us to focus on non-canonical nucleic acid structures, mainly G-quadruplexes, as drug targets. G-quadruplexes have recently been gaining attention due to their involvement in multiple bacterial and viral pathogenesis. Herein, we sought to explore conserved putative G-quadruplex motifs in A. baumannii. In silico analysis revealed the presence of eight conserved motifs in genes involved in bacterial survival and pathogenesis. The biophysical and biomolecular analysis confirmed stable G-quadruplex formation by the motifs and showed a high binding affinity with the well-reported G-quadruplex binding ligand, BRACO-19. BRACO-19 exposure also decreased the growth of bacteria and downregulated the expression of G-quadruplex-harboring genes. The biofilm-forming ability of the bacteria was also affected by BRACO-19 addition. Taking all these observations into account, we have shown here for the first time the potential of G-quadruplex structures as a promising drug target in Acinetobacter baumannii, for addressing the challenges posed by this infamous pathogen.
鲍曼不动杆菌是一种臭名昭著的病原体，通常在医院环境中繁衍生息，是人类众多医院获得性感染的罪魁祸首。其日益严重的多药耐药性使得治疗这种细菌感染的选择相对较少，这是一个重大问题，并促使人们寻找新的方法来解决这一问题。这促使我们专注于非典型核酸结构，主要是 G-四链体，作为药物靶点。由于 G-四链体参与多种细菌和病毒的发病机制，最近它们受到了关注。在此，我们试图探索鲍曼不动杆菌中保守的假定 G-四链体模体。计算机分析显示，参与细菌存活和发病机制的基因中存在八个保守的模体。生物物理和生物分子分析证实了这些模体稳定的 G-四链体形成，并显示出与经过充分报道的 G-四链体结合配体 BRACO-19 具有高结合亲和力。BRACO-19 的暴露也降低了细菌的生长并下调了 G-四链体携带基因的表达。BRACO-19 的添加还影响了细菌的生物膜形成能力。考虑到所有这些观察结果，我们首次表明 G-四链体结构作为鲍曼不动杆菌有希望的药物靶点的潜力，以应对这种臭名昭著的病原体带来的挑战。
