Subramani Nandha Kumar, Venugopal Subhashree
School of Bio Science and Technology, Vellore Institute of Technology, Vellore, Tamil Nadu, India.
Front Bioinform. 2025 Apr 15;5:1562596. doi: 10.3389/fbinf.2025.1562596. eCollection 2025.
The topmost deadliest microorganism, namely, methicillin-resistant (MRSA), causes dreadful infections like bacteremia, pneumonia, endocarditis, and systemic inflammations. The virulence factors associated with MRSA exhibit multidrug-resistant characteristics, complicating treatment choices. So, the primary objective of this study is to identify the MRSA virulence factors and inhibiting its activity utilizing bioinformatic approaches.
The screening of novel therapeutic MRSA targets was conducted based on the predictions retrieved from non-homologous, physicochemical analysis, subcellular localization, druggability, and virulence factor examinations. Following that, flavonoid compounds were docked against specific MRSA targets using AutoDock Vina. Further, molecular dynamic simulations and binding free energy calculations were performed using simulation software.
After examining 2,640 virulence factors that presented in MRSA, the heme response regulator R (HssR) was found to be a novel protein that greatly controls the levels of heme in MRSA infections. Subsequently, the binding energy calculations for flavonoid compounds and HssR revealed that the catechin provided -7.9 kcal/mol, which surpassed the standard drug, namely, vancomycin (-5.9 kcal/mol). Further, the results were validated by evaluating molecular dynamic simulation parameters like RMSD, RMSF, ROG, SASA, and PCA. Through analyzing these parameters, catechin provided a more stable, compact nature and less solvent exposure with HssR than vancomycin. Moreover, the predicted binding free energy for HssR-catechin was found to be -23.0 kcal/mol, which was less compared to the HssR-vancomycin (-16.91 kcal/mol) complex. The results suggested that the catechin was able to modulate the activity of the HssR protein effectively.
These potential findings revealed that heme response regulator R as a promising therapeutic target while the flavonoid compound catechin could act as alternative therapeutic inhibitor that target MRSA infections.
最致命的微生物，即耐甲氧西林金黄色葡萄球菌（MRSA），会引发诸如菌血症、肺炎、心内膜炎和全身性炎症等可怕的感染。与MRSA相关的毒力因子具有多重耐药特性，这使得治疗选择变得复杂。因此，本研究的主要目的是利用生物信息学方法鉴定MRSA毒力因子并抑制其活性。
基于从非同源性、物理化学分析、亚细胞定位、药物可及性和毒力因子检测中获得的预测结果，对新型治疗性MRSA靶点进行筛选。随后，使用AutoDock Vina将黄酮类化合物与特定的MRSA靶点进行对接。此外，使用模拟软件进行分子动力学模拟和结合自由能计算。
在检查了MRSA中呈现的2640个毒力因子后，发现血红素反应调节因子R（HssR）是一种新型蛋白质，它在很大程度上控制着MRSA感染中血红素的水平。随后，黄酮类化合物与HssR的结合能计算表明，儿茶素的结合能为-7.9千卡/摩尔，超过了标准药物万古霉素（-5.9千卡/摩尔）。此外，通过评估诸如均方根偏差（RMSD）、均方根波动（RMSF）、回转半径（ROG）、溶剂可及表面积（SASA）和主成分分析（PCA）等分子动力学模拟参数，验证了结果。通过分析这些参数，发现儿茶素与HssR相比，具有更稳定、紧凑的性质，且与溶剂的接触更少。此外，HssR-儿茶素的预测结合自由能为-23.0千卡/摩尔，与HssR-万古霉素（-16.91千卡/摩尔）复合物相比更低。结果表明，儿茶素能够有效调节HssR蛋白的活性。
这些潜在的发现表明，血红素反应调节因子R是一个有前景的治疗靶点，而黄酮类化合物儿茶素可以作为针对MRSA感染的替代治疗抑制剂。
