Metabolomic fingerprinting, molecular modelling and experimental bioprospection of Helianthus annuus seed cultivars as Pseudomonas aeruginosa LasR modulators

IF 4.5 2区医学 Q1 BIOCHEMISTRY & MOLECULAR BIOLOGY

Bioorganic Chemistry Pub Date : 2025-01-01 DOI:10.1016/j.bioorg.2024.108046

Akshay Raghoonanadan, Yamkela Dweba, Christiana E. Aruwa, Saheed Sabiu

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引用次数: 0

Abstract

The Pseudomonas aeruginosa LasR quorum sensing system (QSS) is central to regulating the expression of several pathogenicity factors. Also, while seed- and/or plant-derived products have been investigated as QSS regulators, the impact of Helianthus annuus (Pannar sunflower seed cultivars) extracts and metabolites as LasR modulators remain underexplored. Thus, this study focused on the untargeted metabolomic profiling (Liquid Chromatography-Mass Spectrometry), in vitro and in silico (docking, pharmacokinetics, dynamic simulation) bioprospection of Pannar seed cultivars’ extracts and metabolites as LasR modulators. The extracts showed significant QS modulating properties (motility, violacein, biofilm, cell attachment, pyocyanin inhibition) with the PAN 7102 CLP seed cultivar (74.3 %) being the most potent, compared to azithromycin (65 %) and cinnamaldehyde (62 %). Chemometric principal component analysis (PCA) analysis showed distinct metabolite signatures with 52.5 % variance across the six cultivars that was driven by aqueous and ethanolic extracts of PAN 7102, 7160, and 7156 cultivars. The presence of methoxymellein, hydroxytetradecanedioic acid, koninginin G, geoside, pinellic acid and methylpicraquassioside A were reported for the first time. The profiled metabolites were subjected to a 100-ns molecular dynamics simulation following molecular docking. Binding free energy (ΔG_bind) calculations revealed obolactone (−48.26 kcal/mol), 1,4-bis(phenylglyoxaloyl)benzene (−45.06 kcal/mol), cyclocanaliculatin (−43.41 kcal/mol), 5-hydroxy-7-methoxy-2-phenylchroman-4-one (−39.18 kcal/mol) and lonchocarpin (−33.78 kcal/mol) as first-time putative leads relative to azithromycin (−32.09 kcal/mol). All lead metabolites also conformed to Lipinski’s rule of 5 (Ro5), and their LasR bound complexes were thermodynamically stable and compact given their strong bond interactions. Findings indicate that metabolomic profiling remain key to identifying new compounds from underexplored species. H. annuus lead metabolites and extracts may also play key roles as LasR modulators. Further structural modification of the 5 leads could aid their development into novel, oral therapeutics targeting LasR to mitigate resistant P. aeruginosa infections.

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铜绿假单胞菌激光r调制剂向日葵种子品种的代谢组学指纹图谱、分子模拟及实验生物展望。

铜绿假单胞菌LasR群体感应系统（QSS）是调控几种致病性因子表达的核心。此外，虽然种子和/或植物衍生产品已被研究作为QSS调节剂，但Helianthus annuus （Pannar葵花籽品种）提取物和代谢物作为LasR调节剂的影响仍未得到充分研究。因此，本研究重点对番石榴种子品种提取物和代谢物作为激光r调节剂的非靶向代谢组学分析（液相色谱-质谱）、体外和计算机（对接、药代动力学、动态模拟）进行生物展望。这些提取物具有显著的QS调节特性（运动、紫紫素、生物膜、细胞附着、抑制pyocyanin），其中PAN 7102 CLP种子品种（74.3%）最有效，而阿奇霉素（65%）和肉桂醛（62%）最强。化学计量主成分分析（PCA）表明，在PAN 7102、7160和7156三个品种的水提液和醇提液驱动下，6个品种的代谢物特征差异显著，方差为52.5%。甲氧基lein、羟基十四烯二酸、丁香素G、geoside、半夏酸、methylpicraquasoside A均为首次报道。在分子对接后，进行了100-ns的分子动力学模拟。结合自由能（ΔGbind）计算结果显示，相对于阿奇霉素（-32.09 kcal/mol），第一次推测的化合物为黑黑内酯（-48.26 kcal/mol）、1,4-二（苯基乙氧酰）苯（-45.06 kcal/mol）、环analiculatin （-43.41 kcal/mol）、5-羟基-7-甲氧基-2-苯基铬-4- 1 （-39.18 kcal/mol）和lonchocarpin （-33.78 kcal/mol）。所有的铅代谢物也符合Lipinski的5规则（Ro5），并且由于它们的强键相互作用，它们的LasR结合配合物热力学稳定且致密。研究结果表明，代谢组学分析仍然是从未开发物种中识别新化合物的关键。铅代谢物和提取物也可能作为激光辐射调节剂发挥重要作用。进一步对这5个先导物进行结构修饰，可能有助于它们发展成为针对激光治疗的新型口服治疗药物，以减轻耐药铜绿假单胞菌感染。

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来源期刊

Bioorganic Chemistry 生物-生化与分子生物学

CiteScore

9.70

自引率

3.90%

发文量

679

审稿时长

31 days

期刊介绍： Bioorganic Chemistry publishes research that addresses biological questions at the molecular level, using organic chemistry and principles of physical organic chemistry. The scope of the journal covers a range of topics at the organic chemistry-biology interface, including: enzyme catalysis, biotransformation and enzyme inhibition; nucleic acids chemistry; medicinal chemistry; natural product chemistry, natural product synthesis and natural product biosynthesis; antimicrobial agents; lipid and peptide chemistry; biophysical chemistry; biological probes; bio-orthogonal chemistry and biomimetic chemistry. For manuscripts dealing with synthetic bioactive compounds, the Journal requires that the molecular target of the compounds described must be known, and must be demonstrated experimentally in the manuscript. For studies involving natural products, if the molecular target is unknown, some data beyond simple cell-based toxicity studies to provide insight into the mechanism of action is required. Studies supported by molecular docking are welcome, but must be supported by experimental data. The Journal does not consider manuscripts that are purely theoretical or computational in nature. The Journal publishes regular articles, short communications and reviews. Reviews are normally invited by Editors or Editorial Board members. Authors of unsolicited reviews should first contact an Editor or Editorial Board member to determine whether the proposed article is within the scope of the Journal.