Pangenome diversification and resistance gene characterization in Salmonella Typhi prioritized RfaJ as a significant therapeutic marker.

IF 3.6 Q2 BIOTECHNOLOGY & APPLIED MICROBIOLOGY Journal, genetic engineering & biotechnology Pub Date : 2023-11-17 DOI:10.1186/s43141-023-00591-w
Kanwal Khan, Khurshid Jalal, Reaz Uddin
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Abstract

Background: Salmonella Typhi stands as the etiological agent responsible for the onset of human typhoid fever. The pressing demand for innovative therapeutic targets against S. Typhi is underscored by the escalating prevalence of this pathogen and the severe nature of its infections. Consequently, this study employs pangenome analysis to scrutinize 119 S. Typhi-resistant strains, aiming to identify the most promising therapeutic targets originating from its core genome.

Results: Subtractive genomics was employed to systematically eliminate non-homologous (n=1147), essential (n=551), drug-like (n=80), and pathogenicity-related (n=18) proteins from the initial pool of 3351 core genome proteins. Consequently, lipopolysaccharide 1,2-glucosyltransferase RfaJ was designated as the optimal pharmacological target due to its potential versatility. Furthermore, a compendium of 9000 FDA-approved compounds was repurposed for evaluation against the RfaJ drug target, with the specific intent of prioritizing novel, high-potency therapeutic candidates for combating S. Typhi. Ultimately, four compounds, namely DB00549 (Zafirlukast), DB15637 (Fluzoparib), DB15688 (Zavegepant), and DB12411 (Bemcentinib), were singled out as potential inhibitors based on the ligand-protein binding affinity (indicated by the lowest anticipated binding energy) and the overall stability of these compounds. Notably, molecular dynamics simulations, conducted over a 50 nanosecond interval, convincingly demonstrated the stability of these compounds in the context of the RfaJ protein.

Conclusion: In summary, the present findings hold significant promise as an initial stride in the broader drug discovery endeavor against S. Typhi infections. However, the experimental validation of the identified drug target and drug candidate is further required to increase the effectiveness of the applied methodology.

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在伤寒沙门菌的泛基因组多样化和耐药基因鉴定中,RfaJ优先作为重要的治疗标记物。
背景:伤寒沙门氏菌是人类伤寒发病的病原。伤寒沙门氏菌的日益流行及其感染的严重性质强调了对创新治疗靶点的迫切需求。因此,本研究采用泛基因组分析来仔细检查119株斑疹伤寒耐药菌株,旨在确定来自其核心基因组的最有希望的治疗靶点。结果:采用减法基因组学技术,系统地从3351个核心基因组蛋白初始库中剔除非同源(n=1147)、必需(n=551)、药物样(n=80)和致病性相关(n=18)蛋白。因此,脂多糖1,2-葡萄糖基转移酶RfaJ由于其潜在的多功能性被指定为最佳的药理学靶标。此外,fda批准的9000种化合物的目录被重新用于针对RfaJ药物靶点的评估,具体目的是优先考虑新的、高效的治疗候选物来对抗伤寒沙门氏菌。最终,基于配体与蛋白质的结合亲和力(预期结合能最低)和整体稳定性,筛选出DB00549 (Zafirlukast)、DB15637 (Fluzoparib)、DB15688 (Zavegepant)和DB12411 (Bemcentinib)四种化合物作为潜在的抑制剂。值得注意的是,在50纳秒的间隔内进行的分子动力学模拟,令人信服地证明了这些化合物在RfaJ蛋白背景下的稳定性。结论:总之,目前的发现具有重要的希望,作为一个初步的跨步在更广泛的药物发现努力对抗伤寒沙门氏菌感染。然而,进一步需要对已确定的药物靶点和候选药物进行实验验证,以提高应用方法的有效性。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
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