背景:肠炎沙门氏菌和鼠伤寒沙门氏菌是非伤寒沙门氏菌感染的主要病原体,造成了巨大的全球卫生负担。这些病原体中抗生素耐药性的出现强调了对创新治疗策略的需求。
目的:使用计算机模拟方法鉴定蛋白质作为针对肠炎沙门氏菌和鼠伤寒沙门氏菌血清型的潜在药物靶标。
方法:在本研究中,我们采用了减法基因组学方法来确定潜在的药物靶点.肠炎沙门氏菌PT4和鼠伤寒沙门氏菌(D23580)的整个蛋白质组,含有393和478种蛋白质,分别,通过减法基因组学进行分析,以鉴定病原体的人类同源蛋白以及与病原体及其宿主共享代谢途径相关的蛋白。
结果:随后的分析揭示了两种菌株共有的19种常见必需蛋白。为了确保主机的特异性,我们鉴定出10种人类不存在的非同源蛋白。在这些蛋白质中,肽聚糖糖基转移酶FtsI是关键的,参与病原体特异性途径,并使其成为有前途的药物靶标。分子对接突出了两个潜在的化合物,BalsamenononA和3,3\',4\',7-四羟基黄酮,与Ftsi有很强的结合亲和力。具有10,000个框架的100ns分子动力学模拟证实了强结合亲和力,并证明了预测化合物在对接部位的持久稳定性。
结论:这项研究的发现为针对沙门氏菌感染的药物开发策略提供了基础。这可以促进针对肠炎沙门氏菌和鼠伤寒沙门氏菌的天然且具有成本效益的药物的前瞻性开发。
BACKGROUND: Salmonella enterica serovar Enteritidis and Salmonella enterica serovar Typhimurium are among the main causative agents of nontyphoidal Salmonella infections, imposing a significant global health burden. The emergence of antibiotic resistance in these pathogens underscores the need for innovative therapeutic strategies.
OBJECTIVE: To identify proteins as potential drug targets against Salmonella Enteritidis and Salmonella Typhimurium serovars using In silico approaches.
METHODS: In this study, a subtractive genomics approach was employed to identify potential drug targets. The whole proteome of Salmonella Enteritidis PT4 and Salmonella Typhimurium (D23580), containing 393 and 478 proteins, respectively, was analyzed through subtractive genomics to identify human homologous proteins of the pathogen and also the proteins linked to shared metabolic pathways of pathogen and its host.
RESULTS: Subsequent analysis revealed 19 common essential proteins shared by both strains. To ensure hostspecificity, we identified 10 non-homologous proteins absent in humans. Among these proteins, peptidoglycan glycosyltransferase FtsI was pivotal, participating in pathogen-specific pathways and making it a promising drug target. Molecular docking highlighted two potential compounds, Balsamenonon A and 3,3\',4\',7-Tetrahydroxyflavylium, with strong binding affinities with FtsI. A 100 ns molecular dynamics simulation having 10,000 frames substantiated the strong binding affinity and demonstrated the enduring stability of the predicted compounds at the docked site.
CONCLUSIONS: The findings in this study provide the foundation for drug development strategies against Salmonella infections, which can contribute to the prospective development of natural and cost-effective drugs targeting Salmonella Enteritidis and Salmonella Typhimurium.