新型抗菌增敏剂的分子设计、合成及生物学活性研究
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摘要
目的：
随着革兰阴性菌对抗菌药物多重耐药性的不断增加，多重耐药的革兰阴性菌感染成为临床病人死亡的主要原因。临床最常见多重耐药革兰阴性菌包括大肠埃希菌、鲍曼不动杆菌、肺炎克雷伯菌、铜绿假单胞菌等，其中大肠埃希菌在ICU病房的分离率高达34%，多重耐药率高达44%。因此，寻找新的有效抗菌药物或者具有提高现有抗菌药物作用的药物（抗菌增敏剂）、研究其作用机制具有重要意义。
AcrAB-TolC属于外排泵RND家族，是导致大肠埃希菌多药耐药的重要因素。在前期研究发现青蒿素衍生物青蒿琥酯具有提高大肠埃希菌对β-内酰胺类抗生素敏感性的作用，其抗菌增敏作用的靶点为大肠埃希菌多药外排泵转运子AcrB，并可抑制AcrBmRNA表达，但其增敏作用强度仍需进一步提高才可能具有临床应用开发价值。因此，本研究拟以AcrB为靶点，运用计算机辅助药物设计（ComputerAided Drug Design,CADD）方法，对青蒿素及其衍生物进行结构设计和改造、并研究其生物学活性，以期得到具有更强抗菌增敏效果的青蒿素衍生物，为新的抗菌增敏剂的研发奠定基础。
方法：
1.采用计算机辅助分子对接的方法模拟青蒿素及其衍生物分子与大肠埃希菌多药外排泵转运子AcrB的结合，以此为依据确立青蒿素衍生物分子结构设计原则；
2.采用化学合成方法合成青蒿素衍生物21个；
3.构建基因重组大肠埃希菌AG100A-AcrB，建立以AcrB为靶点的体外活性定向筛选体系；
4.采用棋盘二倍微孔稀释法对新型青蒿素衍生物增强β-内酰胺类抗生素氨苄西林、头孢呋辛对重组大肠埃希菌AG100A-AcrB的体外抗菌作用进行初筛；
5.采用动态生长曲线法检测具有较强抗菌增敏作用的新型青蒿素衍生物增强氨苄西林、头孢呋辛对重组大肠埃希菌AG100A-AcrB生长的抑制作用进行复筛；
6.采用棋盘二倍微孔稀释法和动态生长曲线法观察新型青蒿素衍生物DHA-7联合氨苄西林对大肠埃希菌ATCC35218的抗菌增敏作用；
7.采用半定量RT-PCR检测青蒿素衍生物DHA-7联合氨苄西林对大肠埃希菌ATCC35218多药外排泵转运子AcrB及其调控子表达的影响；
8.采用Realtime PCR检测检测青蒿素衍生物DHA-7联合氨苄西林对大肠埃希菌ATCC35218多药外排泵转运子AcrB及其调控子表达的影响。
结果：
1.青蒿素及其衍生物与大肠埃希菌多药外排泵转运子AcrB的分子对接结果表明，青蒿素及其衍生物与AcrB分子主要通过青蒿素母核结合。对比观察三个分子的对接结果，可以发现青蒿琥酯和双氢青蒿素的位置几乎相同。青蒿琥酯的支链部分在活性中心中很好的伸展，使得青蒿琥酯几乎不可能出现类似青蒿素的结合方式。所以，可以假设青蒿琥酯的琥酯支链部分对于其与AcrB活性中心的结合有重要作用。它可以阻止药物分子结合到活性中心，并且可以阻隔活性中心附近的药物通道，从而切断药物的运输。此外，Gln176和Ser46可以通过氢键连接来固定这三个分子的骨架结构。
2.依据分子对接结果，进行结构设计，以青蒿素母核结构为基础进行结构改造，合成了21个青蒿素衍生物，其中17个为新化合物。
3.经体外抗菌增敏活性筛选，得到了具有较强抗菌增敏活性的新型青蒿素衍生物DHA-7；
4.半定量RT-PCR及Realtime-PCR结果均表明，新型青蒿素衍生物DHA-7单独作用，对大肠埃希菌多药外排泵转运子AcrB及其上游调控子的表达并没有明显影响。而相对于单纯的氨苄西林（8μg/mL）处理，256μg/mL DHA-7联合8μg/mL氨苄西林可明显减少AcrB及其上游正向调控子SoxS、MarA等的表达水平，同时，青蒿素衍生物联合氨苄西林对于负向调控子AcrR、MppA的表达没有明显影响。
结论：
经以大肠埃希菌多药外排泵转运子AcrB为靶点进行计算机辅助分子对接，设计合成了21个青蒿素衍生物，其中17个为新化合物。经体外筛选得到新型青蒿素衍生物DHA-7。新型青蒿素衍生物DHA-7具有增强β-内酰胺类抗生素氨苄西林、头孢呋辛对大肠埃希菌的抗菌作用。初步机制研究表明，DHA-7通过显著下调大肠埃希菌多药外排泵转运子AcrB及其上游正向调控子如MarA和SoxS等的表达，发挥对β-内酰胺类抗生素氨苄西林的抗菌增敏作用。
Objective：
The infection caused by multi-drug resistance gram-negative bacteria is one of themain death cause of patients. The common multi-drug resistance G-bacteria strains includeEscherichia coli (E. coli), Acinetobacter baumannii, Klebsiella pneumoniae andPseudomonas aeruginosa. A serious phenomenon is34%of clinical isolates are E. coli inintensive care units, and44%of those are multi-drug resistance. In view of this, it seemsmore important to discover new efficient anti-E. coli drugs or antibacterial sensitizer.
AcrAB-TolC, a resistance-nodulation-cell-division (RND) superfamily derived effluxpump system, plays a very important role for multi-drug resistance in E. coli. Previously,we demonstrated that artesunate (AS), an artemisinin (ART) derivant, significantlyincreased the antibacterial effect of β-lactam antibiotics against E. coli via decreasing AcrBmRNA expression. The aim of the present study plan to obtain new antibacterial sensitizerwith better bioactivities targeting AcrB, using ART and its derivatives AS anddihydroartemisinin (DHA) as direct chemicals to design and synthesize new derivants. Andthe bioactivity of new ART derivants will be also studied.
Methods：
1. The molecular interactions between AcrB, ART or its derivants were computermodelled by molecular docking method. The structures of new molecules were designedbased on the interaction details.
2. Twenty-one ART derivants were synthesized by side chain modifications.
3. Construction of recombinant E. coli AG100A-AcrB which used as in vitrobioactivity screening system targeting AcrB.
4. Two-fold diluted method was used to measure the susceptibility of E. coliAG100A-AcrB to various β-lactam antibiotics ampicillin or cefuroxime in the absence orpresence of new ART derivants.
5. Dynamic growth assays of effects of ampicillin or cefuroxime alone or combinedwith new ART derivants on E. coli AG100A-AcrB.
6. Dynamic growth assays of effects of ampicillin or cefuroxime alone or combinedwith DHA-7on E. coli ATCC35218.
7. Semi-quantitative RT-PCR analysis of the mRNA levels of AcrB and upstreamregulators within ATCC35218after the treatment of DHA-7combined with ampicillin.
8．Realtime PCR analysis of the mRNA levels of AcrB and upstream regulators withinATCC35218after the treatment of the treatment of DHA-7combined with ampicillin.
Results：
1. The molecular docking results suggested the three candidate ligands could dock intoAcrB very well by immobilizing the parent sesquiterpene lactone nuclear to Gln176andSer46. In the most favored docking mode, although three ligands had the same parentsesquiterpene lactone structure, only DHA and AS had the same docking poses, while ARTwas different from the two derivants. The succinic acid ester tail of AS could extended inthe drug transport tunnel of the AcrB very well. It was pretended to prevent the drug bind tothe active center and then block the drug efflux tunnel.
2. The sesquiterpene lactone nuclear was used as the pharmacophore based on themolecular docking results, and the side chain was modified to obtain twenty-one ARTderivants, seventeen of which were new structures.
3. DHA-7was considered to be the best antibacterial sensitizer according to the invitro bioavtivity evaluations.
4. Semi-quantitative RT-PCR and Realtime PCR results demonstrated that althoughDHA-7itselves could not change the mRNA expressions of AcrB and its upstreamregulators of ATCC35218, while DHA-7combined with ampicillin could significantlydecrease the mRNA expressions of AcrB and its upstream positive regulators, MarA, Rob,FIS, etc. Meanwhile, the results also suggested that DHA-7combined with ampicillin didnot decrease AcrB expression by change the negative regulators, AcrR, MppA, etc.
Conclusions：
New ART derivants targeting multi-drug efflux pump transportor AcrB of E. coli wasdesigned using molecular docking method based on computer modeling. Twenty-one newART derivants were synthesized, and seventeen of which were new structures. DHA-7was considered to be the best antibacterial sensitizer according to the in vitro evaluations.DHA-7could increase the sensibility of E. coli to ampicillin or cefuroxime throughsignificantly decreased mRNA expression of multi-drug efflux pump transporter AcrBcombined with antibiotics. The results also suggested the inhibition of AcrB might beassociated with the decreased mRNA expressions of AcrB positive regulators, MarA, Roband FIS, etc.
随着革兰阴性菌对抗菌药物多重耐药性的不断增加，多重耐药的革兰阴性菌感染成为临床病人死亡的主要原因。临床最常见多重耐药革兰阴性菌包括大肠埃希菌、鲍曼不动杆菌、肺炎克雷伯菌、铜绿假单胞菌等，其中大肠埃希菌在ICU病房的分离率高达34%，多重耐药率高达44%。因此，寻找新的有效抗菌药物或者具有提高现有抗菌药物作用的药物（抗菌增敏剂）、研究其作用机制具有重要意义。
AcrAB-TolC属于外排泵RND家族，是导致大肠埃希菌多药耐药的重要因素。在前期研究发现青蒿素衍生物青蒿琥酯具有提高大肠埃希菌对β-内酰胺类抗生素敏感性的作用，其抗菌增敏作用的靶点为大肠埃希菌多药外排泵转运子AcrB，并可抑制AcrBmRNA表达，但其增敏作用强度仍需进一步提高才可能具有临床应用开发价值。因此，本研究拟以AcrB为靶点，运用计算机辅助药物设计（ComputerAided Drug Design,CADD）方法，对青蒿素及其衍生物进行结构设计和改造、并研究其生物学活性，以期得到具有更强抗菌增敏效果的青蒿素衍生物，为新的抗菌增敏剂的研发奠定基础。
方法：
1.采用计算机辅助分子对接的方法模拟青蒿素及其衍生物分子与大肠埃希菌多药外排泵转运子AcrB的结合，以此为依据确立青蒿素衍生物分子结构设计原则；
2.采用化学合成方法合成青蒿素衍生物21个；
3.构建基因重组大肠埃希菌AG100A-AcrB，建立以AcrB为靶点的体外活性定向筛选体系；
4.采用棋盘二倍微孔稀释法对新型青蒿素衍生物增强β-内酰胺类抗生素氨苄西林、头孢呋辛对重组大肠埃希菌AG100A-AcrB的体外抗菌作用进行初筛；
5.采用动态生长曲线法检测具有较强抗菌增敏作用的新型青蒿素衍生物增强氨苄西林、头孢呋辛对重组大肠埃希菌AG100A-AcrB生长的抑制作用进行复筛；
6.采用棋盘二倍微孔稀释法和动态生长曲线法观察新型青蒿素衍生物DHA-7联合氨苄西林对大肠埃希菌ATCC35218的抗菌增敏作用；
7.采用半定量RT-PCR检测青蒿素衍生物DHA-7联合氨苄西林对大肠埃希菌ATCC35218多药外排泵转运子AcrB及其调控子表达的影响；
8.采用Realtime PCR检测检测青蒿素衍生物DHA-7联合氨苄西林对大肠埃希菌ATCC35218多药外排泵转运子AcrB及其调控子表达的影响。
结果：
1.青蒿素及其衍生物与大肠埃希菌多药外排泵转运子AcrB的分子对接结果表明，青蒿素及其衍生物与AcrB分子主要通过青蒿素母核结合。对比观察三个分子的对接结果，可以发现青蒿琥酯和双氢青蒿素的位置几乎相同。青蒿琥酯的支链部分在活性中心中很好的伸展，使得青蒿琥酯几乎不可能出现类似青蒿素的结合方式。所以，可以假设青蒿琥酯的琥酯支链部分对于其与AcrB活性中心的结合有重要作用。它可以阻止药物分子结合到活性中心，并且可以阻隔活性中心附近的药物通道，从而切断药物的运输。此外，Gln176和Ser46可以通过氢键连接来固定这三个分子的骨架结构。
2.依据分子对接结果，进行结构设计，以青蒿素母核结构为基础进行结构改造，合成了21个青蒿素衍生物，其中17个为新化合物。
3.经体外抗菌增敏活性筛选，得到了具有较强抗菌增敏活性的新型青蒿素衍生物DHA-7；
4.半定量RT-PCR及Realtime-PCR结果均表明，新型青蒿素衍生物DHA-7单独作用，对大肠埃希菌多药外排泵转运子AcrB及其上游调控子的表达并没有明显影响。而相对于单纯的氨苄西林（8μg/mL）处理，256μg/mL DHA-7联合8μg/mL氨苄西林可明显减少AcrB及其上游正向调控子SoxS、MarA等的表达水平，同时，青蒿素衍生物联合氨苄西林对于负向调控子AcrR、MppA的表达没有明显影响。
结论：
经以大肠埃希菌多药外排泵转运子AcrB为靶点进行计算机辅助分子对接，设计合成了21个青蒿素衍生物，其中17个为新化合物。经体外筛选得到新型青蒿素衍生物DHA-7。新型青蒿素衍生物DHA-7具有增强β-内酰胺类抗生素氨苄西林、头孢呋辛对大肠埃希菌的抗菌作用。初步机制研究表明，DHA-7通过显著下调大肠埃希菌多药外排泵转运子AcrB及其上游正向调控子如MarA和SoxS等的表达，发挥对β-内酰胺类抗生素氨苄西林的抗菌增敏作用。
Objective：
The infection caused by multi-drug resistance gram-negative bacteria is one of themain death cause of patients. The common multi-drug resistance G-bacteria strains includeEscherichia coli (E. coli), Acinetobacter baumannii, Klebsiella pneumoniae andPseudomonas aeruginosa. A serious phenomenon is34%of clinical isolates are E. coli inintensive care units, and44%of those are multi-drug resistance. In view of this, it seemsmore important to discover new efficient anti-E. coli drugs or antibacterial sensitizer.
AcrAB-TolC, a resistance-nodulation-cell-division (RND) superfamily derived effluxpump system, plays a very important role for multi-drug resistance in E. coli. Previously,we demonstrated that artesunate (AS), an artemisinin (ART) derivant, significantlyincreased the antibacterial effect of β-lactam antibiotics against E. coli via decreasing AcrBmRNA expression. The aim of the present study plan to obtain new antibacterial sensitizerwith better bioactivities targeting AcrB, using ART and its derivatives AS anddihydroartemisinin (DHA) as direct chemicals to design and synthesize new derivants. Andthe bioactivity of new ART derivants will be also studied.
Methods：
1. The molecular interactions between AcrB, ART or its derivants were computermodelled by molecular docking method. The structures of new molecules were designedbased on the interaction details.
2. Twenty-one ART derivants were synthesized by side chain modifications.
3. Construction of recombinant E. coli AG100A-AcrB which used as in vitrobioactivity screening system targeting AcrB.
4. Two-fold diluted method was used to measure the susceptibility of E. coliAG100A-AcrB to various β-lactam antibiotics ampicillin or cefuroxime in the absence orpresence of new ART derivants.
5. Dynamic growth assays of effects of ampicillin or cefuroxime alone or combinedwith new ART derivants on E. coli AG100A-AcrB.
6. Dynamic growth assays of effects of ampicillin or cefuroxime alone or combinedwith DHA-7on E. coli ATCC35218.
7. Semi-quantitative RT-PCR analysis of the mRNA levels of AcrB and upstreamregulators within ATCC35218after the treatment of DHA-7combined with ampicillin.
8．Realtime PCR analysis of the mRNA levels of AcrB and upstream regulators withinATCC35218after the treatment of the treatment of DHA-7combined with ampicillin.
Results：
1. The molecular docking results suggested the three candidate ligands could dock intoAcrB very well by immobilizing the parent sesquiterpene lactone nuclear to Gln176andSer46. In the most favored docking mode, although three ligands had the same parentsesquiterpene lactone structure, only DHA and AS had the same docking poses, while ARTwas different from the two derivants. The succinic acid ester tail of AS could extended inthe drug transport tunnel of the AcrB very well. It was pretended to prevent the drug bind tothe active center and then block the drug efflux tunnel.
2. The sesquiterpene lactone nuclear was used as the pharmacophore based on themolecular docking results, and the side chain was modified to obtain twenty-one ARTderivants, seventeen of which were new structures.
3. DHA-7was considered to be the best antibacterial sensitizer according to the invitro bioavtivity evaluations.
4. Semi-quantitative RT-PCR and Realtime PCR results demonstrated that althoughDHA-7itselves could not change the mRNA expressions of AcrB and its upstreamregulators of ATCC35218, while DHA-7combined with ampicillin could significantlydecrease the mRNA expressions of AcrB and its upstream positive regulators, MarA, Rob,FIS, etc. Meanwhile, the results also suggested that DHA-7combined with ampicillin didnot decrease AcrB expression by change the negative regulators, AcrR, MppA, etc.
Conclusions：
New ART derivants targeting multi-drug efflux pump transportor AcrB of E. coli wasdesigned using molecular docking method based on computer modeling. Twenty-one newART derivants were synthesized, and seventeen of which were new structures. DHA-7was considered to be the best antibacterial sensitizer according to the in vitro evaluations.DHA-7could increase the sensibility of E. coli to ampicillin or cefuroxime throughsignificantly decreased mRNA expression of multi-drug efflux pump transporter AcrBcombined with antibiotics. The results also suggested the inhibition of AcrB might beassociated with the decreased mRNA expressions of AcrB positive regulators, MarA, Roband FIS, etc.
引文
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