具有多靶向功能的加替沙星(Gatifloxacin)芳香杂环铜(II)配合物,可用于抗菌治疗和对抗抗生素耐药性。

IF 4.5 2区 医学 Q1 BIOCHEMISTRY & MOLECULAR BIOLOGY Bioorganic Chemistry Pub Date : 2024-11-06 DOI:10.1016/j.bioorg.2024.107938
Xiao-Yin Wu, Qi-Yan Liu, Shan Jiang, Zheng-Yin Pan, Jia-Hao Dong, Bai-Hua Chen, Jin-Hao Li, Ya-Shu Liu, Yingju Liu, Liang He
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引用次数: 0

摘要

近年来,新型抗生素的开发速度相对缓慢,加剧了抗生素耐药性问题的紧迫性。因此,科学家们将注意力转向了通过抗生素与金属元素的配位来增强抗生素的活性。本研究以加替沙星为基础,设计并合成了三种新型抗菌铜复合物。这些复合物具有很强的抗菌活性,尤其是 Cu-1,对金黄色葡萄球菌(S.aureus)的最小抑菌浓度(MIC)仅为 0.063 μg/mL,显示出很强的抑菌能力。进一步的研究揭示了复合物 Cu-1 的抗菌机制,发现它不仅能抑制 DNA 回旋酶和拓扑异构酶 IV 的活性,还能有效抑制生物膜的形成并破坏细胞膜的完整性。这种多靶点作用有助于降低细菌产生抗药性的风险。此外,Cu-1 与传统抗生素之间的协同作用通过棋盘试验得到了证实,为抗菌治疗提供了新的策略。使用小鼠金黄色葡萄球菌感染模型进行的体内实验证明了 Cu-1 的显著抗菌功效,为其治疗金黄色葡萄球菌感染的潜力提供了有力支持。这项研究表明,铜、加替沙星和合适的芳香杂环配体形成的配位复合物对细菌具有多靶点特性,为抗菌治疗中对抗抗生素耐药性提供了新的方向。
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Copper(II) aromatic heterocyclic complexes of Gatifloxacin with multi-targeting capabilities for antibacterial therapy and combating antibiotic resistance.

In recent years, the pace of novel antibiotic development has been relatively slow, intensifying the urgency of the antibiotic resistance issue. Consequently, scientists have turned their attention to enhancing antibiotic activity by coordinating antibiotics with metal elements. This study designs and synthesizes three novel antibacterial copper complexes based on Gatifloxacin. These complexes exhibit potent antibacterial activity, notably Cu-1, with a minimum inhibitory concentration (MIC) of only 0.063 μg/mL against Staphylococcus aureus (S.aureus), demonstrating potent bacteriostatic capabilities. Further investigations unveil the antibacterial mechanisms of complex Cu-1, revealing its ability not only to suppress the activities of DNA gyrase and topoisomerases IV, but also to effectively inhibit biofilm formation and disrupt the integrity of cell membrane. This multi-targeting action contributes to mitigating the risk of bacterial resistance emergence. Additionally, synergy between Cu-1 and conventional antibiotics is confirmed through checkerboard assays, offering novel strategies for antibacterial therapy. In vivo experiments using a murine model of S.aureus infection demonstrate the significant antibacterial efficacy of Cu-1, providing robust support for its potential in treating S.aureus infections. This study demonstrates that the coordination complexes formed by copper, Gatifloxacin and suitable aromatic heterocyclic ligands exhibit multi-targeting characteristics against bacteria, offering a new direction for combating antibiotic resistance in antibacterial therapy.

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来源期刊
Bioorganic Chemistry
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.
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