Department of Biophysics, All India Institute of Medical Sciences, New Delhi 110029, India.
Department of Computer Science, Jamia Millia Islamia, New Delhi 110025, India.
Int J Biol Macromol. 2020 Sep 15;159:1073-1083. doi: 10.1016/j.ijbiomac.2020.05.063. Epub 2020 May 15.
Drug repurposing is an efficient alternative approach to counter the increasing drug-resistant pathogens to treat infectious diseases. FtsZ is an essential bacterial cytokinesis protein involved in the formation of cell-division complex and targeting FtsZ using FDA approved drugs is a promising strategy to identify and develop a new antibacterial drug. Using in silico pharmacophore-based screening of drug bank, molecular docking and molecular dynamics simulations, we identified six drugs inhibiting the function of stFtsZ from Salmonella Typhi. The selected drugs target stFtsZ at the hydrophobic cleft formed between the C-terminal domain and helix α7 with binding energy better than -8 kcal/mol. Out of these six drugs, benzethonium chloride showed promising results at 8 μM concentration where it inhibits stFtsZ GTPase activity by 80% and prevents polymerization. Benzethonium chloride also possesses an excellent antibacterial activity against the bacterial culture of Salmonella Typhi (ATCC 19430), Staphylococcus aureus (ATCC 43300) and Escherichia coli (ATCC 25922) with the MIC values of 8 μg/mL, 1 μg/mL and 12 μg/mL, respectively. Based on our current study, the scaffold of benzethonium chloride can be used for the development of broad-spectrum antibacterial agents against drug-resistant pathogens.
药物重定位是一种有效的替代方法，可用于应对不断增加的耐药病原体，以治疗传染病。FtsZ 是一种参与细胞分裂复合物形成的必需细菌胞质分裂蛋白，使用 FDA 批准的药物靶向 FtsZ 是一种有前途的策略，可以识别和开发新的抗菌药物。我们通过计算机药物化学基于药效团的药物库筛选、分子对接和分子动力学模拟，从伤寒沙门氏菌中鉴定出六种抑制 stFtsZ 功能的药物。所选药物靶向 stFtsZ 在 C 端结构域和螺旋 α7 之间形成的疏水性裂缝，结合能优于-8 kcal/mol。在这六种药物中，苯扎氯铵在 8 μM 浓度下显示出有希望的结果，它抑制 stFtsZ GTPase 活性 80%并阻止聚合。苯扎氯铵还对伤寒沙门氏菌（ATCC 19430）、金黄色葡萄球菌（ATCC 43300）和大肠杆菌（ATCC 25922）的细菌培养物具有出色的抗菌活性，其 MIC 值分别为 8 μg/mL、1 μg/mL 和 12 μg/mL。基于我们目前的研究，苯扎氯铵的支架可用于开发针对耐药病原体的广谱抗菌药物。
