Discovering novel inhibitors of RfaH from Klebsiella pneumoniae to combat antimicrobial resistance

IF 2.3 3区 生物学 Q3 MICROBIOLOGY
Mohammad Umar Saeed, Shazia Ahmed, Arunabh Choudhury, Afzal Hussain, Mohamed F. Alajmi, Taj Mohammad, Md. Imtaiyaz Hassan
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Abstract

RfaH is a crucial protein involved in anti-termination of transcription, which is necessary for spreading virulence in certain types of bacteria, such as Klebsiella pneumoniae and Escherichia coli. RfaH works by interacting directly with RNA polymerase and ribosomes, which activates the production of certain components needed for the bacteria's survival. Targeting RfaH offers a novel approach to hindering bacterial transcription and virulence. In this study, we performed computational screening of the IMPPAT 2.0 database consisting of 17,967 natural compounds, which were filtered based on Lipinski’s RO5 filter, selecting only those that had druglike properties. We performed virtual screening on the remaining 11,708 druglike phytochemicals and selected those having strong binding affinity and specificity, leading to the identification of top hits. These hits were further evaluated based on their pharmacokinetic features like PAINS filter, pharmacokinetic properties, pan assay interference, and interaction analysis. Finally, three phytochemicals, Withanone, Withametelin B, and Ixocarpanolide were identified as potential inhibitors for RfaH, having appreciable affinity of − 9.0, − 9.0 and − 8.8 kcal/mol specificity towards the binding pocket of RfaH. An all-atom molecular dynamic simulation was carried out for 500 ns to examine the structural flexibility and dynamic stability of RfaH and RfaH-ligand complexes, which revealed that complexes maintained stability throughout the given duration. All the selected compounds have shown drug-like properties as predicted from ADMET analysis and their physicochemical parameters. These compounds selectively bind to the crucial binding sites of RfaH and interact with important residues, preventing its binding with RNAP which can further be exploited as potential lead molecules against RfaH, providing a promising therapeutic avenue for combating antibiotic resistance.

从肺炎克雷伯氏菌中发现新型 RfaH 抑制剂,以对抗抗菌药耐药性。
RfaH 是一种参与反转录终止的关键蛋白质,是肺炎克雷伯氏菌和大肠杆菌等某些类型细菌传播毒性的必要条件。RfaH 直接与 RNA 聚合酶和核糖体相互作用,从而激活细菌生存所需的某些成分的生产。以 RfaH 为靶标提供了一种阻碍细菌转录和毒力的新方法。在这项研究中,我们对 IMPPAT 2.0 数据库中的 17,967 种天然化合物进行了计算筛选,并根据利宾斯基的 RO5 过滤器对这些化合物进行了筛选,只选出那些具有类似药物特性的化合物。我们对剩余的 11,708 种类似药物的植物化学物质进行了虚拟筛选,选出了那些具有较强结合亲和力和特异性的化合物,从而确定了热门化合物。我们根据其药代动力学特征(如 PAINS 过滤器、药代动力学特性、泛检测干扰和相互作用分析)对这些新发现进行了进一步评估。最后,Withanone、Withametelin B 和 Ixocarpanolide 这三种植物化学物质被确定为 RfaH 的潜在抑制剂,它们对 RfaH 结合口袋的亲和力分别为 - 9.0、- 9.0 和 - 8.8 kcal/mol 。为了研究 RfaH 和 RfaH 配体复合物的结构灵活性和动态稳定性,我们进行了 500 ns 的全原子分子动态模拟,结果表明复合物在整个给定时间内保持稳定。根据 ADMET 分析及其理化参数的预测,所有选定的化合物都具有类似药物的性质。这些化合物可选择性地与 RfaH 的关键结合位点结合,并与重要残基相互作用,阻止 RfaH 与 RNAP 结合。
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来源期刊
Archives of Microbiology
Archives of Microbiology 生物-微生物学
CiteScore
4.90
自引率
3.60%
发文量
601
审稿时长
3 months
期刊介绍: Research papers must make a significant and original contribution to microbiology and be of interest to a broad readership. The results of any experimental approach that meets these objectives are welcome, particularly biochemical, molecular genetic, physiological, and/or physical investigations into microbial cells and their interactions with their environments, including their eukaryotic hosts. Mini-reviews in areas of special topical interest and papers on medical microbiology, ecology and systematics, including description of novel taxa, are also published. Theoretical papers and those that report on the analysis or ''mining'' of data are acceptable in principle if new information, interpretations, or hypotheses emerge.
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