Molecular dynamics simulation of the complex PBP-2x with drug cefuroxime to explore the drug resistance mechanism of Streptococcus suis R61.
Molecular dynamics simulation of the complex PBP-2x with drug cefuroxime to explore the drug resistance mechanism of Streptococcus suis R61.
复制标题
药物头孢呋辛复合物PBP-2x分子动力学模拟探讨猪链球菌R61耐药机制
DOI：
10.1371/journal.pone.0035941
复制
发表时间：
2012
期刊：
影响因子：
3.7
通讯作者：
Yu J
中科院分区：
文献类型：
--
作者：
Ge Y;Wu J;Xia Y;Yang M;Xiao J;Yu J
猪链球菌的耐药性是人类和猪的世界性难题。已有研究指出，青霉素结合蛋白(PBPS)突变是导致β-内酰胺类抗生素耐药的重要原因之一。在这项研究中，我们使用分子动力学(MD)方法研究了头孢呋辛(CES)和PBP2x在两个新测序的猪链球菌中的相互作用差异：药物敏感株A7和耐药株R61。MM-PBSA结果表明，药物在A7(PBP2x-A7)中与PBP2x的结合比在R61(PBP2x-R61)中结合得更紧密。这与两株菌对头孢呋辛的耐药性明显不同是一致的。氢键分析表明，PBP2x-A7优先与头孢呋辛结合，而不是与PBP2x-R61结合。药物与PBP2x-A7形成了三个稳定的氢键，而药物与PBP2x-R61之间只有一个不稳定的氢键。此外，通过成对能量分解比较，我们发现Gln569、Tyr594和Gly596残基是直接导致不同结合的关键突变残基。通过研究药物的结合模式，我们发现突变残基Ala320、Gln553和Thr595通过拓扑构象变化间接影响最终现象。最重要的是，我们的结果揭示了这两个PBP2x蛋白与药物头孢呋辛之间的特定相互作用的一些细节。这在一定程度上解释了猪链球菌的耐药机制，有助于进一步的药物设计或改进。
Drug resistance of Streptococcus suis strains is a worldwide problem for both humans and pigs. Previous studies have noted that penicillin-binding protein (PBPs) mutation is one important cause of β-lactam antibiotic resistance. In this study, we used the molecular dynamics (MD) method to study the interaction differences between cefuroxime (CES) and PBP2x within two newly sequenced Streptococcus suis: drug-sensitive strain A7, and drug-resistant strain R61. The MM-PBSA results proved that the drug bound much more tightly to PBP2x in A7 (PBP2x-A7) than to PBP2x in R61 (PBP2x-R61). This is consistent with the evidently different resistances of the two strains to cefuroxime. Hydrogen bond analysis indicated that PBP2x-A7 preferred to bind to cefuroxime rather than to PBP2x-R61. Three stable hydrogen bonds were formed by the drug and PBP2x-A7, while only one unstable bond existed between the drug and PBP2x-R61. Further, we found that the Gln569, Tyr594, and Gly596 residues were the key mutant residues contributing directly to the different binding by pair wise energy decomposition comparison. By investigating the binding mode of the drug, we found that mutant residues Ala320, Gln553, and Thr595 indirectly affected the final phenomenon by topological conformation alteration. Above all, our results revealed some details about the specific interaction between the two PBP2x proteins and the drug cefuroxime. To some degree, this explained the drug resistance mechanism of Streptococcus suis and as a result could be helpful for further drug design or improvement.
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DOI：
10.1073/pnas.89.22.10915
发表时间：
1992-11-15
影响因子：
11.1
作者：
HENIKOFF, S;HENIKOFF, JG
通讯作者：
HENIKOFF, JG
影响因子：
6.1
作者：
CONNOLLY, ML
通讯作者：
CONNOLLY, ML
影响因子：
4.9
作者：
Antonio Escudero, Jose;San Millan, Alvaro;Gonzalez-Zorn, Bruno
通讯作者：
Gonzalez-Zorn, Bruno
影响因子：
3.3
作者：
Martel, A;Baele, M;Haesebrouck, F
通讯作者：
Haesebrouck, F
影响因子：
1.5
作者：
CANTIN, M;HAREL, J;GOTTSCHALK, M
通讯作者：
GOTTSCHALK, M