山楂抗菌增敏活性物质的定向分离及生物学活性研究
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摘要
目的：
耐甲氧西林金黄色葡萄球菌(Methicillin-resistant staphylococcus aureus, MRSA)是临床常见的病原菌，治疗棘手，死亡率高，已成为严重的临床医学及公共卫生问题。自1961年首次发现MRSA以来，MRSA成为医院感染重要的革兰阳性细菌，多重耐药现象日益严重，呈现出对除糖肽类抗生素之外的其他抗菌药物，特别是β-内酰胺类抗生素的高水平耐药。万古霉素是治疗MRSA感染的“最后防线”，但近年来，国外部分地区已相继检出对万古霉素耐药（Vancomycin-resistant staphylococcus aureus, VRSA）或中介的金黄色葡萄球菌(Vancomycin-intermediary staphylococcus aureus, VISA)。因此，基于MRSA的耐药机制研究有效的治疗措施具有重要意义。
MRSA对抗生素的主要耐药机制为：①表达特殊的青霉素结合蛋白------PBP2a，PBP2a可以代偿被抗生素抑制了的青霉素结合蛋白的转肽酶活性，从而维持细菌细胞壁的合成；②产生β-内酰胺酶，β-内酰胺酶利用其活性位点的丝氨酸水解β-内酰胺环，水解β-内酰胺类抗生素而致耐药；③增强的细菌主动外排系统，以减少抗生素在菌体内积聚。
目前，针对MRSA的耐药机制而研发抗MRSA感染的药物主要有两种策略：一是直接抗菌策略。包括全新结构化合物的发现和对现有抗生素结构的修饰，但全新结构化合物的发现需要较长周期，而对现有抗生素结构的修饰如替考拉宁并未体现出较万古霉素更好的疗效。二是间接抗菌策略。即研究具有增强现有抗生素作用的药物，称之为抗菌增敏剂。这类药物它们本身并不具有抗菌活性，但可恢复细菌对现有抗生素的敏感性、减少现有抗生素的使用量，并减少耐药菌株的产生。因此，新型抗菌增敏剂的研究是目前研究的焦点与热点。
来自天然植物的化合物是新型抗菌增敏剂的源泉。中药长期用于感染性疾病的治疗，为寻找新型抗菌增敏剂提供了丰富的资源。
本课题组前期已建立定向分离化学物质的技术平台，即利用生物传感器技术将PBP2a蛋白成功包被于生物传感器样品池上，用于筛选与PBP2a具有高亲和力的中药。本研究以标准菌株MRSA为研究对象，首先以PBP2a为靶点从78种传统中药中筛选出与PBP2a具有高亲和力的中药；其次以体外抗菌增敏活性为导向，从与PBP2a具有高亲和力的中药中筛选出具有最佳抗菌增敏活性的中药—山楂；然后以山楂为研究对象，进行具有抗菌增敏活性物质的定向分离、体内外生物学活性研究及其抗菌增敏作用机制初步研究。
方法：
1.将天然药化分离手段与生物学活性评价相结合，从山楂中定向分离具有抗菌增敏活性的组分和单体化合物
2.活性化合物或组分的体外药效学研究
2.1正交实验筛选具有最佳抗菌增敏活性的化合物配伍和配伍比，命名最佳配伍比的化合物为CE
2.2微孔二倍稀释法测定活性化合物与抗生素的FICI
3. CE的体内生物学活性研究
建立亚致死剂量WHO-2攻击小鼠脓毒症模型，观察CE联合苯唑西林对亚致死剂量WHO-2攻击小鼠脓毒症模型外周血中细菌数量和前炎症细胞因子、C-反应蛋白、前降钙素水平的影响
4. CE抗菌增敏作用机制的初步研究
4.1利用生物传感器技术观察CE与PBP2a的亲和力；RT-PCR方法观察CE对mecA基因表达的影响
4.2. nitrocefin法观察CE对WHO-2菌β-内酰胺酶的影响
4.3激光共聚焦、荧光分光光度法观察CE对柔红霉素在WHO-2内聚集的影响；RT-PCR法观察CE对WHO-2细菌外排泵基因表达的影响
4.4透射电镜技术观察CE对WHO-2菌细胞壁形态的影响
4.5利用Trixton-X诱导WHO-2自溶后，观察CE对细菌自溶速率的影响；RT-PCR技术观察CE对WHO-2菌自溶相关基因表达的影响
结果：
1.以PBP2a和抗菌增敏活性为导向，从78种中药中筛选得到具有稳定的抗菌增敏活性的山楂水提物
2.从山楂中定向分离得到具有最佳抗菌增敏活性的化合物组分CP；从CP中分离得到3个单体化合物，经结构解析后确认为（+）-儿茶素（简称为C）、（-）-表儿茶素没食子酸酯（简称为ECg）和（-）-表没食子儿茶素（简称为EGC）
3.活性化合物或组分的体外、体内药效学研究
3.1具有最佳抗菌增敏活性的化合物配伍质量比为8:1，即C128μg/mL、ECg16μg/mL，将8:1配伍的C和ECg命名为CE
3.2CE可增加45株MRSA临床分离株对6种β-内酰胺类抗生素（苯唑西林，氨苄西林，舒氨西林，头孢唑林，头孢吡肟和亚胺培南/西司他丁）的敏感性
3.3CE可降低亚致死剂量WHO-2攻击小鼠脓毒症模型的外周血中细菌数量和前炎症因子TNF-α、CRP、PCT的水平
4. CE抗菌增敏作用机制的初步研究
4.1C、ECg与PBP2a蛋白的亲和力均较低，且不影响mecA基因的表达
4.2. CE不影响WHO-2菌β-内酰胺酶的活性
4.3CE可增加抗生素在WHO-2菌体内的聚集，该作用可能与其下调WHO-2外排泵基因norA、norC和abcA的表达有关
4.4CE影响WHO-2细菌的分裂、降低WHO-2的自溶速率，该作用可能与其下调ssaA、lytM、saeS、vraS和sarA等自溶相关基因的表达有关
Objective：
Methicillin-resistant Staphylococcus aureus (MRSA) is one of the principal multi-resistant pathogens causing serious infections associated with high morbidity and mortality.Since isolated in1961, MRSA had been one of important gram-positive pathogens in clinic.In fact, MRSA is resistant to almost all kinds of antibiotics especially to β-lactam antibiotics.Vancomycin is the most used antibiotics for MRSA infection, and is considered as “lastdefense line”. However, the strains of Staphylococcus aureus resistant to vancomycin (VRSA)and vancomycin-intermediary staphylococcus aureus (VISA) have been detected in USA andother countries. Therefore, it is very important to search for effective treatments based on thebacterial resistance mechanisms.
The main resistance mechanisms of MRSA against antibiotics include:①acquisition ofthe mecA gene that encodes the penicillin-binding protein2a (PBP2a) with low affinity toβ-lactam antibiotics,②large expression of β-lactamase to destroy β-lactams by hydrolysis,and③expressions of efflux pumps in order to extrude antibiotics.
To date, there are two strategies to overcome MRSA resistance. One is directlyantimicrobial strategy including new structures’ compounds and modified compoundsderivatived from present antibiotics. However, the discovery of new structures’ compoundsneeds a longer period and derivatives such as teicoplanin doesn’t display much bettereffective than parent compound vancomycin. Another one is indirect antimicrobial strategynamed as antibacterial enhancer. This kind of agents itself has no antibacterial effect but it canrestore the pathogen’s sensitivity to present antibiotics, decreases the dosage of presentantibiotics, and reduces the emergence of resistance bacteria. Therefore, new antibacterialenhancer has become the focus in the field of antibacterial agents.
Natural products from plants are the treasure-house of the new antibacterial enhancers.Traditional Chinese herbs have been used for thousands year to treat infection, which is thesource of new antibacterial enhancers.
Previously, we have established a directional separation platform for new antibacterialenhancers. PBP2a was coated on the surface of biosensor in order to screen the herbs withaffinity for PBP2a. At the present, MRSA strains were selected as objective. Firstly,Traditional Chinese herbs with high affinity for PBP2a were screened from seventy-eightherbs based on target of PBP2a. Secondary, Fructus Crataegi was screened from the herbswith high affinity for PBP2a under the guide of antibacterial enhancer’s activity. And then thecompounds with good activities was isolated from the extract, their activities wereinvestigated in vitro and in vivo, and the possible mechanisms were also investigated.
Methods：
1. The directional isolation of compositions and compounds from Fructus Crataegibased on the combination of pharmaceutical chemistry methods and bioactivity assays
2. The investigation of compositions and monomers in vitro
2.1Determination of combination of compounds with best bioactivity and their ratio, thecombination was named as CE.
2.2Determination of FIC of the compounds combined with antibiotics usingmicrodilution method.
3. The investigation of compositions in vitro
After establishment of sepsis mice model challenged with sublethal live MRSA, bloodbacteria number, serum CRP, PCT and TNF-α levels were tested.
4. The preliminary investigation of antibacterial enhancement mechanisms
4.1Measurement of affinity of CE for PBP2a using affinity biosensor technology.Influences of CE on mecA gene expression were observed using RT-PCR method.
4.2Influence of CE on β-lactamase activity was measured by nitrocefin method.
4.3Influences of CE on accumulation of daunorubicin within bacteria treated with CEwere observed using both confocal scanning microscopy and fluorospectrophotometry methods.And then effect of CE on efflux system of WHO-2was measured by RT-PCR method.
4.4Effect of CE on the autolysis rate of WHO-2treated with Triton-X-100was measured and then effect of CE on the genes expression of autolysins and its regulators weremeasured using RT-PCR method.
Results：
1. The water extraction of Fructus Crataegi which had stable antibacterial enhancementwas screened out from78Traditional Chinese herbs under the guides of PBPa2-target andbioactivity.
2. Three compounds were isolated from water extraction of Fructus Crataegi, they wereidentified as (+)-catechin (C),(-)-epicatechin gallate (ECg) and (-)-epigallatecatechin (EGC)after structure confirmation.
3. The investigation of Pharmacological activities of compositions in vitro and in vivo.
3.1The combination ratio with best bioactivity was8:1, including128μg/mL of C and16μg/mL of ECg. This combination was named as CE.
3.2CE specifically enhanced antibacterial activities of six kinds of β-lactam antibioticsagainst forty-five clinical MRSA strains.
3.3CE in combination with oxacillin markedly decreased whole blood bacterial load,CRP, PCT and TNF-α levels of mice challenged with sublethal WHO-2.
4. The preliminary investigation of antibacterial enhancement mechanisms
4.1C and ECg had no high affinity for PBP2a, and they didn’t inhibit mecA geneexpression.
4.2CE had no influence on the activity of β-lactamase.
4.3CE increased daunorubicin accumulation within WHO-2, which might be related tothe down-regulation of mRNA expressions of efflux pumps.
4.4CE inhibited bacterial division, decrease autolysis rate of WHO-2, which might berelated to the down-regulation of mRNA expressions of autolysins and its regulators.
耐甲氧西林金黄色葡萄球菌(Methicillin-resistant staphylococcus aureus, MRSA)是临床常见的病原菌，治疗棘手，死亡率高，已成为严重的临床医学及公共卫生问题。自1961年首次发现MRSA以来，MRSA成为医院感染重要的革兰阳性细菌，多重耐药现象日益严重，呈现出对除糖肽类抗生素之外的其他抗菌药物，特别是β-内酰胺类抗生素的高水平耐药。万古霉素是治疗MRSA感染的“最后防线”，但近年来，国外部分地区已相继检出对万古霉素耐药（Vancomycin-resistant staphylococcus aureus, VRSA）或中介的金黄色葡萄球菌(Vancomycin-intermediary staphylococcus aureus, VISA)。因此，基于MRSA的耐药机制研究有效的治疗措施具有重要意义。
MRSA对抗生素的主要耐药机制为：①表达特殊的青霉素结合蛋白------PBP2a，PBP2a可以代偿被抗生素抑制了的青霉素结合蛋白的转肽酶活性，从而维持细菌细胞壁的合成；②产生β-内酰胺酶，β-内酰胺酶利用其活性位点的丝氨酸水解β-内酰胺环，水解β-内酰胺类抗生素而致耐药；③增强的细菌主动外排系统，以减少抗生素在菌体内积聚。
目前，针对MRSA的耐药机制而研发抗MRSA感染的药物主要有两种策略：一是直接抗菌策略。包括全新结构化合物的发现和对现有抗生素结构的修饰，但全新结构化合物的发现需要较长周期，而对现有抗生素结构的修饰如替考拉宁并未体现出较万古霉素更好的疗效。二是间接抗菌策略。即研究具有增强现有抗生素作用的药物，称之为抗菌增敏剂。这类药物它们本身并不具有抗菌活性，但可恢复细菌对现有抗生素的敏感性、减少现有抗生素的使用量，并减少耐药菌株的产生。因此，新型抗菌增敏剂的研究是目前研究的焦点与热点。
来自天然植物的化合物是新型抗菌增敏剂的源泉。中药长期用于感染性疾病的治疗，为寻找新型抗菌增敏剂提供了丰富的资源。
本课题组前期已建立定向分离化学物质的技术平台，即利用生物传感器技术将PBP2a蛋白成功包被于生物传感器样品池上，用于筛选与PBP2a具有高亲和力的中药。本研究以标准菌株MRSA为研究对象，首先以PBP2a为靶点从78种传统中药中筛选出与PBP2a具有高亲和力的中药；其次以体外抗菌增敏活性为导向，从与PBP2a具有高亲和力的中药中筛选出具有最佳抗菌增敏活性的中药—山楂；然后以山楂为研究对象，进行具有抗菌增敏活性物质的定向分离、体内外生物学活性研究及其抗菌增敏作用机制初步研究。
方法：
1.将天然药化分离手段与生物学活性评价相结合，从山楂中定向分离具有抗菌增敏活性的组分和单体化合物
2.活性化合物或组分的体外药效学研究
2.1正交实验筛选具有最佳抗菌增敏活性的化合物配伍和配伍比，命名最佳配伍比的化合物为CE
2.2微孔二倍稀释法测定活性化合物与抗生素的FICI
3. CE的体内生物学活性研究
建立亚致死剂量WHO-2攻击小鼠脓毒症模型，观察CE联合苯唑西林对亚致死剂量WHO-2攻击小鼠脓毒症模型外周血中细菌数量和前炎症细胞因子、C-反应蛋白、前降钙素水平的影响
4. CE抗菌增敏作用机制的初步研究
4.1利用生物传感器技术观察CE与PBP2a的亲和力；RT-PCR方法观察CE对mecA基因表达的影响
4.2. nitrocefin法观察CE对WHO-2菌β-内酰胺酶的影响
4.3激光共聚焦、荧光分光光度法观察CE对柔红霉素在WHO-2内聚集的影响；RT-PCR法观察CE对WHO-2细菌外排泵基因表达的影响
4.4透射电镜技术观察CE对WHO-2菌细胞壁形态的影响
4.5利用Trixton-X诱导WHO-2自溶后，观察CE对细菌自溶速率的影响；RT-PCR技术观察CE对WHO-2菌自溶相关基因表达的影响
结果：
1.以PBP2a和抗菌增敏活性为导向，从78种中药中筛选得到具有稳定的抗菌增敏活性的山楂水提物
2.从山楂中定向分离得到具有最佳抗菌增敏活性的化合物组分CP；从CP中分离得到3个单体化合物，经结构解析后确认为（+）-儿茶素（简称为C）、（-）-表儿茶素没食子酸酯（简称为ECg）和（-）-表没食子儿茶素（简称为EGC）
3.活性化合物或组分的体外、体内药效学研究
3.1具有最佳抗菌增敏活性的化合物配伍质量比为8:1，即C128μg/mL、ECg16μg/mL，将8:1配伍的C和ECg命名为CE
3.2CE可增加45株MRSA临床分离株对6种β-内酰胺类抗生素（苯唑西林，氨苄西林，舒氨西林，头孢唑林，头孢吡肟和亚胺培南/西司他丁）的敏感性
3.3CE可降低亚致死剂量WHO-2攻击小鼠脓毒症模型的外周血中细菌数量和前炎症因子TNF-α、CRP、PCT的水平
4. CE抗菌增敏作用机制的初步研究
4.1C、ECg与PBP2a蛋白的亲和力均较低，且不影响mecA基因的表达
4.2. CE不影响WHO-2菌β-内酰胺酶的活性
4.3CE可增加抗生素在WHO-2菌体内的聚集，该作用可能与其下调WHO-2外排泵基因norA、norC和abcA的表达有关
4.4CE影响WHO-2细菌的分裂、降低WHO-2的自溶速率，该作用可能与其下调ssaA、lytM、saeS、vraS和sarA等自溶相关基因的表达有关
Objective：
Methicillin-resistant Staphylococcus aureus (MRSA) is one of the principal multi-resistant pathogens causing serious infections associated with high morbidity and mortality.Since isolated in1961, MRSA had been one of important gram-positive pathogens in clinic.In fact, MRSA is resistant to almost all kinds of antibiotics especially to β-lactam antibiotics.Vancomycin is the most used antibiotics for MRSA infection, and is considered as “lastdefense line”. However, the strains of Staphylococcus aureus resistant to vancomycin (VRSA)and vancomycin-intermediary staphylococcus aureus (VISA) have been detected in USA andother countries. Therefore, it is very important to search for effective treatments based on thebacterial resistance mechanisms.
The main resistance mechanisms of MRSA against antibiotics include:①acquisition ofthe mecA gene that encodes the penicillin-binding protein2a (PBP2a) with low affinity toβ-lactam antibiotics,②large expression of β-lactamase to destroy β-lactams by hydrolysis,and③expressions of efflux pumps in order to extrude antibiotics.
To date, there are two strategies to overcome MRSA resistance. One is directlyantimicrobial strategy including new structures’ compounds and modified compoundsderivatived from present antibiotics. However, the discovery of new structures’ compoundsneeds a longer period and derivatives such as teicoplanin doesn’t display much bettereffective than parent compound vancomycin. Another one is indirect antimicrobial strategynamed as antibacterial enhancer. This kind of agents itself has no antibacterial effect but it canrestore the pathogen’s sensitivity to present antibiotics, decreases the dosage of presentantibiotics, and reduces the emergence of resistance bacteria. Therefore, new antibacterialenhancer has become the focus in the field of antibacterial agents.
Natural products from plants are the treasure-house of the new antibacterial enhancers.Traditional Chinese herbs have been used for thousands year to treat infection, which is thesource of new antibacterial enhancers.
Previously, we have established a directional separation platform for new antibacterialenhancers. PBP2a was coated on the surface of biosensor in order to screen the herbs withaffinity for PBP2a. At the present, MRSA strains were selected as objective. Firstly,Traditional Chinese herbs with high affinity for PBP2a were screened from seventy-eightherbs based on target of PBP2a. Secondary, Fructus Crataegi was screened from the herbswith high affinity for PBP2a under the guide of antibacterial enhancer’s activity. And then thecompounds with good activities was isolated from the extract, their activities wereinvestigated in vitro and in vivo, and the possible mechanisms were also investigated.
Methods：
1. The directional isolation of compositions and compounds from Fructus Crataegibased on the combination of pharmaceutical chemistry methods and bioactivity assays
2. The investigation of compositions and monomers in vitro
2.1Determination of combination of compounds with best bioactivity and their ratio, thecombination was named as CE.
2.2Determination of FIC of the compounds combined with antibiotics usingmicrodilution method.
3. The investigation of compositions in vitro
After establishment of sepsis mice model challenged with sublethal live MRSA, bloodbacteria number, serum CRP, PCT and TNF-α levels were tested.
4. The preliminary investigation of antibacterial enhancement mechanisms
4.1Measurement of affinity of CE for PBP2a using affinity biosensor technology.Influences of CE on mecA gene expression were observed using RT-PCR method.
4.2Influence of CE on β-lactamase activity was measured by nitrocefin method.
4.3Influences of CE on accumulation of daunorubicin within bacteria treated with CEwere observed using both confocal scanning microscopy and fluorospectrophotometry methods.And then effect of CE on efflux system of WHO-2was measured by RT-PCR method.
4.4Effect of CE on the autolysis rate of WHO-2treated with Triton-X-100was measured and then effect of CE on the genes expression of autolysins and its regulators weremeasured using RT-PCR method.
Results：
1. The water extraction of Fructus Crataegi which had stable antibacterial enhancementwas screened out from78Traditional Chinese herbs under the guides of PBPa2-target andbioactivity.
2. Three compounds were isolated from water extraction of Fructus Crataegi, they wereidentified as (+)-catechin (C),(-)-epicatechin gallate (ECg) and (-)-epigallatecatechin (EGC)after structure confirmation.
3. The investigation of Pharmacological activities of compositions in vitro and in vivo.
3.1The combination ratio with best bioactivity was8:1, including128μg/mL of C and16μg/mL of ECg. This combination was named as CE.
3.2CE specifically enhanced antibacterial activities of six kinds of β-lactam antibioticsagainst forty-five clinical MRSA strains.
3.3CE in combination with oxacillin markedly decreased whole blood bacterial load,CRP, PCT and TNF-α levels of mice challenged with sublethal WHO-2.
4. The preliminary investigation of antibacterial enhancement mechanisms
4.1C and ECg had no high affinity for PBP2a, and they didn’t inhibit mecA geneexpression.
4.2CE had no influence on the activity of β-lactamase.
4.3CE increased daunorubicin accumulation within WHO-2, which might be related tothe down-regulation of mRNA expressions of efflux pumps.
4.4CE inhibited bacterial division, decrease autolysis rate of WHO-2, which might berelated to the down-regulation of mRNA expressions of autolysins and its regulators.
引文
1. Mera, R.M., et al., Increasing role of Staphylococcus aureus and community-acquiredmethicillin-resistant Staphylococcus aureus infections in the United States: a10-yeartrend of replacement and expansion. Microb Drug Resist,2011.17(2):321-8.
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