Department of Medical Microbiology and Parasitology, Faculty of Medicine, King Abdulaziz University, Jeddah 21589, Saudi Arabia.
Department of Hematology/Oncology, Yousef Abdulatif Jameel Scientific Chair of Prophetic Medicine Application, Faculty of Medicine, King Abdulaziz University, Jeddah 21589, Saudi Arabia.
Int J Environ Res Public Health. 2022 Nov 10;19(22):14812. doi: 10.3390/ijerph192214812.
is a novel, multidrug-resistant pathogen belonging to the Enterobacter genus and has the ability to acquire resistance to multiple antibiotic classes. However, there is currently no registered drug on the market that has been shown to be effective. Hence, there is an urgent need to identify novel therapeutic targets and effective treatments for . In the current study, a bacterial pan genome analysis and subtractive proteomics approach was employed to the core proteomes of six strains of using several bioinformatic tools, software, and servers. However, 2611 nonredundant proteins were predicted from the 21,720 core proteins of core proteome. Out of 2611 nonredundant proteins, 372 were obtained from Geptop2.0 as essential proteins. After the subtractive proteomics and subcellular localization analysis, only 133 proteins were found in cytoplasm. All cytoplasmic proteins were examined using BLASTp against the virulence factor database, which classifies 20 therapeutic targets as virulent. Out of these 20, 3 cytoplasmic proteins: ferric iron uptake transcriptional regulator (FUR), UDP-2,3diacylglucosamine diphosphatase (UDP), and lipid-A-disaccharide synthase (lpxB) were chosen as potential drug targets. These drug targets are important for bacterial survival, virulence, and growth and could be used as therapeutic targets. More than 2500 plant chemicals were used to molecularly dock these proteins. Furthermore, the lowest-binding energetic docked compounds were found. The top five hit compounds, , , , and demonstrated optimum binding against all three target proteins. Furthermore, molecular dynamics simulations and MM/GBSA analyses validated the stability of ligand-protein complexes and revealed that these compounds could serve as potential replication inhibitors. Consequently, this study marks a significant step forward in the creation of new and powerful drugs against . Future studies should validate these targets experimentally to prove their function in survival and virulence.
是一种新型的、多药耐药的病原体，属于肠杆菌属，能够获得对多种抗生素类别的耐药性。然而，目前市场上没有注册的药物被证明是有效的。因此，迫切需要为 确定新的治疗靶点和有效治疗方法。在本研究中，采用细菌泛基因组分析和消减蛋白质组学方法，使用几种生物信息学工具、软件和服务器，对 6 株菌株的核心蛋白质组进行了研究。然而，从核心蛋白质组的 21720 个核心蛋白质中预测出了 2611 个非冗余蛋白质。在 2611 个非冗余蛋白质中，有 372 个是从 Geptop2.0 中获得的必需蛋白质。经过消减蛋白质组学和亚细胞定位分析，只有 133 个蛋白质存在于细胞质中。所有细胞质蛋白都使用 BLASTp 与毒力因子数据库进行了比较，该数据库将 20 个治疗靶点归类为毒力。在这 20 个中，有 3 个细胞质蛋白：铁摄取转录调节因子（FUR）、UDP-2,3 二酰基葡萄糖二磷酸酶（UDP）和脂酰二糖合酶（lpxB）被选为潜在的药物靶点。这些药物靶点对细菌的生存、毒力和生长都很重要，可以作为治疗靶点。使用超过 2500 种植物化学物质对这些蛋白质进行了分子对接。此外，还找到了最低结合能的对接化合物。排名前五的命中化合物 、 、 、 和 对所有 3 个靶蛋白都表现出最佳结合。此外，分子动力学模拟和 MM/GBSA 分析验证了配体-蛋白复合物的稳定性，并表明这些化合物可以作为潜在的 复制抑制剂。因此，本研究在开发针对 的新型强效药物方面迈出了重要的一步。未来的研究应该通过实验验证这些靶点，以证明它们在 生存和毒力中的作用。
Zotero 插件
