发现异苦参素是一种ATC酶结合先导物，对耐甲氧西林金黄色葡萄球菌具有强效活性
{"_":"Discovery of isokurarinone as an ATCase-engaging lead with potent activity against methicillin-resistant .","i":["Staphylococcus aureus"]}
摘要(中文译文)
耐甲氧西林金黄色葡萄球菌（MRSA）的全球扩散仍是导致难治性感染的重要因素，凸显了利用新机制疗法的迫切需求。天冬氨酸转氨甲酰酶（ATCase）催化嘧啶生物合成的首个关键步骤，是一个有前景的代谢靶点，可能与MRSA的适应性和持续性相关。通过基于结构的虚拟筛选和实验验证，我们鉴定出黄酮类化合物异苦参酮为靶向ATCase的化合物，表现出强效的抗MRSA活性。对接和分子动力学模拟，以及表面等离子体共振和差示扫描荧光法，为直接结合提供了证据，并伴随表达下降和ATCase活性降低。非靶向代谢组学揭示嘧啶核苷酸稳态被破坏，同时伴有膜完整性受损、质子动力势降低、细胞内ATP水平下降和氧化应激增加。异苦参酮还与万古霉素表现出相加作用，抑制生物膜形成并改变毒力相关基因的表达。安全性评估显示在哺乳动物细胞中具有细胞类型依赖性的细胞毒性，而在小鼠单次剂量2 g/kg下未观察到明显的急性口服毒性。在MRSA感染伤口的小鼠模型中，异苦参酮加速伤口闭合、减少细菌负荷并减轻局部炎症介质。总体而言，这些发现支持ATCase作为MRSA代谢导向靶点的观点，并提名异苦参酮作为治疗开发的有前景的先导骨架。
Abstract
The global proliferation of methicillin-resistant (MRSA) persists as a significant contributor to challenging infections, highlighting the urgent necessity for therapies that utilize novel mechanisms. Aspartate transcarbamoylase (ATCase), which catalyzes the initial committed step of pyrimidine biosynthesis, represents a promising metabolic target with potential relevance to MRSA fitness and persistence. Through structure-based virtual screening and experimental validation, we identified the flavonoid isokurarinone as a compound targeting ATCase, demonstrating potent anti-MRSA activity. Docking and molecular dynamics simulations, along with surface plasmon resonance and differential scanning fluorimetry, provided evidence for direct binding, which was accompanied by a decrease in expression and a reduction in ATCase activity. Non-targeted metabolomics revealed a disruption of pyrimidine nucleotide homeostasis, coinciding with impaired membrane integrity, reduced proton motive force, decreased intracellular ATP levels, and increased oxidative stress. Isokurarinone also showed an additive interaction with vancomycin , inhibited biofilm formation and altered the expression of virulence-associated genes. Safety evaluation showed cell-type-dependent cytotoxicity in mammalian cells, while no obvious acute oral toxicity was observed in mice at a single dose of 2 g/kg. In a murine model of MRSA-infected wounds, isokurarinone accelerated wound closure, reduced bacterial burden, and attenuated local inflammatory mediators. Collectively, these findings support the notion of ATCase as a metabolism-guided target for MRSA and nominate isokurarinone as a promising lead scaffold for therapeutic development.
如何引用
AMA
Xinyuan Cao, Xiaorong Yang, Lixia Dai, Xueyan Liu, Zile Gong, Xiaoyan Yu, et al. {"_":"Discovery of isokurarinone as an ATCase-engaging lead with potent activity against methicillin-resistant .","i":["Staphylococcus aureus"]}. Virulence. 2026; doi:10.1080/21505594.2026.2707766.
APA
Xinyuan Cao, Xiaorong Yang, Lixia Dai, Xueyan Liu, Zile Gong, Xiaoyan Yu, et al (2026). {"_":"Discovery of isokurarinone as an ATCase-engaging lead with potent activity against methicillin-resistant .","i":["Staphylococcus aureus"]}. Virulence. https://doi.org/10.1080/21505594.2026.2707766
GB/T 7714
Xinyuan Cao, Xiaorong Yang, Lixia Dai, Xueyan Liu, Zile Gong, Xiaoyan Yu, et al. {"_":"Discovery of isokurarinone as an ATCase-engaging lead with potent activity against methicillin-resistant .","i":["Staphylococcus aureus"]}[J]. Virulence, 2026 doi:10.1080/21505594.2026.2707766.
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