穿心莲内酯磺化物抗耐甲氧西林金黄色葡萄球菌及其生物膜的药效及机制

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中文摘要：目的探讨穿心莲内酯磺化物(andrographolide sulfonate,AS)抗耐甲氧西林金黄色葡萄球菌(methicillin resistant staphylococcus aureus,MRSA)及其生物膜(biofilm,BF)的药效及机制.方法采用微量肉汤倍比稀释法测定 AS 对 MRSA 的最低抑菌浓度(minimum inhibition concentration,MIC);生长曲线法测定不同浓度AS作用MRSA 24 小时内的细菌时间—生长曲线;微孔板法测定不同剂量AS给药对成熟MRSA生物膜(MRSA biofilm,MRSA-BF)活菌量的影响;扫描电镜(scanning electron microscope,SEM)观察不同剂量AS对成熟MRSA-BF的形态学变化;通过超高压液相色谱—飞行时间质谱仪法(UPLC-TOF-MS)分析不同剂量AS干预成熟MRSA-BF菌体的内源性代谢物谱特征.结果 AS 表现出显著的抗 MRSA 活性,MIC 为 50 mg/mL;12.5 mg/mL 和6.25 mg/mL浓度的AS均可较好地抑制MRSA及其BF的生长,破坏已成熟的膜性结构,且抑制作用呈剂量依赖关系.代谢组学结果提示27 个内源性终端代谢物是反映生物膜形成的代谢物,相关的生物通路有苯丙氨酸(phenylalanine,PA)、酪氨酸(tyrosine,Tyr)、色氨酸的生物合成以及牛磺酸和亚牛磺酸代谢;16 个内源性终端代谢物是6.25 mg/mL AS干预MRSA-BF的代谢标志物,相关的生物通路为苯丙氨酸、酪氨酸和色氨酸的生物合成;18 个内源性终端代谢物是 12.5 mg/mL AS干预MRSA-BF的代谢标志物,通路分析未发现相关的生物通路;11 个内源性终端代谢物是反映AS干预MRSA-BF的药效代谢标志物,其相关的生物通路包括苯丙氨酸、酪氨酸和色氨酸的生物合成、新生霉素的生物合成以及苯丙氨酸的代谢.结论 AS对MRSA及其成熟生物膜均有抑制作用,抑制BF的机制与细菌苯丙氨酸、酪氨酸和色氨酸的生物合成、新生霉素的生物合成以及苯丙氨酸的代谢相关.AS可作为临床治疗MRSA-BF感染的潜在有效方案.

外文标题：Effect and mechanism of andrographolide sulfonate against methicillin resistant staphylococcus aureus and its biofilm

外文摘要：Objective To investigate the drug efficacy and mechanism of andrographolide sulfonate(AS)against Methicillin resistant Staphylococcus aureus(MRSA)and its biofilm(BF).Methods The minimum inhibitory concentration(MIC)of AS against MRSA was determined using micro broth dilution method;the growth curve method was used to measure the bacterial time growth curve of MRSA treated with different concentrations of AS within 24 h;different doses of AS were introduced to mature MRSA-BF;scanning electron microscopy(SEM)was used to observe the morphological changes of mature MRSA-BF treated with different doses of AS;the endogenous metabolite profile characteristics of mature MRSA-BF cells with different doses of AS intervention were analyzed using ultra-high pressure liquid chromatography-time of flight mass spectrometry(UPLC-TOF-MS).Results AS showed significant anti-MRSA activity and the MIC was 50 mg/mL.Both 12.5 mg/mL and 6.25 mg/mL concentrations of AS can effectively inhibit the growth of MRSA and its mature BF,destroy the mature membrane structure,and the inhibitory effect is dose-dependent.The results of metabolomics showed that 27 endogenous terminal metabolites were metabolites reflecting biofilm formation,and the related biological pathways were Phenylalanine,tyrosine and tryptophan biosynthesis and Taurine and hypotaurine metabolism.The 16 endogenous terminal metabolites were metabolic markers of 6.25 mg/mL AS intervention on MRSA-BF and the related biological pathway was Phenylalanine,tyrosine and tryptophan biosynthesis.The 18 endogenous terminal metabolites were metabolic markers of 12.5 mg/mL AS intervention on MRSA-BF,and no relevant biological pathway was found in pathway analysis.The 11 endogenous terminal metabolites are metabolic markers reflecting the efficacy of AS intervention on MRSA-BF.In addition,the related biological pathways include the Phenylalanine,tyrosine and tryptophan biosynthesis,Novobiocin biosynthesis and Phenylalanine metabolism.Conclusion The mature biofilm of AS can inhibit MRSA.The mechanism of inhibiting the biofilm is related to the biosynthesis of phenylalanine,tyrosine and tryptophan,the biosynthesis of neomycin and the metabolism of phenylalanine.AS can be used as a potentially effective scheme for the clinical treatment of infection caused by MRSA-BF.

外文关键词：

andrographolide sulfonatemethicillin resistant staphylococcus aureusbiofilmmetabolomicspharmacodynamics mechanism

作者：

温博、冯小玉、张璐璐、李丽、Tariq Mahmood、吕诚、杨伟峰、谭勇

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作者单位：

100700 北京,中国中医科学院中医临床基础医学研究所

巴基斯坦真纳大学植物科学系

中国中医科学院医学实验中心

关键词：

穿心莲内酯磺化物耐甲氧西林金黄色葡萄球菌生物膜代谢组学药效机制

基金：

中国中医科学院第十四期自主选题项目中国中医科学院国际合作项目国家中医药多学科交叉创新团队项目中国中医科学院科技创新工程中医临床基础学科创新团队项目中国中医科学院科技创新工程中医临床基础学科重大攻关项目子课题

项目编号：

Z0735GH201909ZYYCXTD-D-202005CI2021B003CI2021A00704-2

出版年：

2024

DOI：

10.3969/j.issn.1674-1749.2024.09.007

环球中医药

中华国际医学交流基金会

环球中医药

CSTPCD

影响因子：1.553

ISSN：1674-1749

年,卷(期)：2024.17(9)