de Oliveira Paola Dias, Martins Allana Cristina Faustino, da Silva Gomes Roberto, Beatriz Adilson, Alcantara Glaucia Braz, Micheletti Ana Camila
LP2 Laboratory, Institute of Chemistry, Federal University of Mato Grosso Do Sul, Campo Grande, Brazil.
Department of Pharmaceutical Sciences, North Dakota State University, Fargo, ND, USA.
Metabolomics. 2024 Dec 4;21(1):2. doi: 10.1007/s11306-024-02197-w.
The knowledge of the mode of action of an antimicrobial is essential for drug development and helps to fight against bacterial resistance. Thus, it is crucial to use analytical techniques to study the mechanism of action of substances that have potential to act as antibacterial agents OBJECTIVE: To use NMR-based metabolomics combined with chemometrics and molecular docking to identify the metabolic responses of Staphylococcus aureus following exposure to commercial antibiotics and some synthesized ω-aminoalkoxylxanthones.
Intracellular metabolites of S. aureus were extracted after treatment with four commercial antibiotics and three synthesized ω-aminoalkoxylxanthones. NMR spectra were obtained and H NMR data was analyzed using both unsupervised and supervised algorithms (PCA and PLS-DA, respectively). Docking simulations on DNA topoisomerase IV protein were also performed for the ω-aminoalkoxylxanthones.
Through chemometric analysis, we distinguished between the control group and antibiotics with extracellular (ampicillin) and intracellular targets (kanamycin, tetracycline, and ciprofloxacin). We identified 21 metabolites, including important metabolites that differentiate the groups, such as betaine, acetamide, glutamate, lysine, alanine, isoleucine/leucine, acetate, threonine, proline, and ethanol. Regarding the xanthone-type derivatives (S6, S7 and S8), we observed a greater similarity between S7 and ciprofloxacin, which targets bacterial DNA replication. The molecular docking analysis showed high affinity of the ω-aminoalkoxylxanthones with the topoisomerase IV enzyme, as well as ciprofloxacin.
NMR-based metabolomics has shown to be an effective technique to assess the metabolic profile of S. aureus after treatment with certain antimicrobial compounds, helping the investigation of their mechanism of action.
了解抗菌剂的作用模式对于药物开发至关重要，并有助于对抗细菌耐药性。因此，使用分析技术研究具有抗菌剂潜力的物质的作用机制至关重要。目的：运用基于核磁共振的代谢组学结合化学计量学和分子对接技术，确定金黄色葡萄球菌在接触商业抗生素和一些合成的ω-氨基烷氧基呫吨酮后的代谢反应。
用四种商业抗生素和三种合成的ω-氨基烷氧基呫吨酮处理金黄色葡萄球菌后，提取其细胞内代谢物。获得核磁共振谱，并分别使用无监督和有监督算法（分别为PCA和PLS-DA）分析氢核磁共振数据。还对ω-氨基烷氧基呫吨酮进行了DNA拓扑异构酶IV蛋白的对接模拟。
通过化学计量学分析，我们区分了对照组与具有细胞外靶点（氨苄青霉素）和细胞内靶点（卡那霉素、四环素和环丙沙星）的抗生素。我们鉴定出21种代谢物，包括区分不同组别的重要代谢物，如甜菜碱、乙酰胺、谷氨酸、赖氨酸、丙氨酸、异亮氨酸/亮氨酸、乙酸盐、苏氨酸、脯氨酸和乙醇。关于呫吨酮类衍生物（S6、S7和S8），我们观察到S7与靶向细菌DNA复制的环丙沙星之间有更大的相似性。分子对接分析表明，ω-氨基烷氧基呫吨酮与拓扑异构酶IV酶以及环丙沙星具有高亲和力。
基于核磁共振的代谢组学已被证明是一种有效的技术，可用于评估金黄色葡萄球菌在经某些抗菌化合物处理后的代谢谱，有助于研究其作用机制。
