A secondary drug resistance mutation of TEM-1 beta-lactamase that suppresses misfolding and aggregation.
A secondary drug resistance mutation of TEM-1 beta-lactamase that suppresses misfolding and aggregation.
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TEM-1 β-内酰胺酶的二次耐药突变可抑制错误折叠和聚集。
DOI：
10.1073/pnas.98.1.283
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发表时间：
2001
影响因子：
11.1
通讯作者：
Gilbert,HF
中科院分区：
文献类型：
--
作者：
Sideraki,V;Huang,W;Palzkill,T;Gilbert,HF
在革兰氏阴性菌中，TEM1β-内酰胺酶提供了质粒介导的β-内酰胺类耐药的主要机制。由于使用了超广谱β-内酰胺类抗生素(如头孢他啶)和β-内酰胺酶抑制剂(如克拉维酸)，出现了对抗生素耐药性增加的天然TEM1变种。一些变异酶在催化β-内酰胺水解方面更有效，而另一些酶对抑制剂更具抵抗力。M182T是在两种类型的变异型TEM1β-内酰胺酶中观察到的替换。这种突变只有在与其他氨基酸替代结合时才被发现，这表明它可能纠正由其他突变引入的缺陷，这些突变改变了特异性。工程核心突变L76N使周质β-内酰胺酶活性降低100倍，作为一个模型来理解M182T突变的抑制机制。对L76N酶单独和与M182T突变联合作用的生化研究表明，M182T替代作用于折叠水平，但不影响β-内酰胺酶的热力学稳定性。因此，M182T替换是一个自然发生的突变的例子，这种突变已经进化到改变蛋白质的折叠途径，并在耐药性的进化过程中赋予选择性优势。
In Gram-negative bacteria, TEM-1 β-lactamase provides the major mechanism of plasmid-mediated β-lactam resistance. Natural variants of TEM-1 with increased antibiotic resistance have appeared in response to the use of extended-spectrum β-lactam antibiotics (e.g., ceftazidime) and β-lactamase inhibitors (e.g., clavulanic acid). Some of the variant enzymes are more efficient at catalyzing β-lactam hydrolysis, whereas others are more resistant to inhibitors. M182T is a substitution observed in both types of variant TEM-1 β-lactamases. This mutation is found only in combination with other amino acid substitutions, suggesting that it may correct defects introduced by other mutations that alter the specificity. An engineered core mutation, L76N, which diminishes the periplasmic β-lactamase activity by 100-fold, was used as a model to understand the mechanism of suppression of the M182T mutation. Biochemical studies of the L76N enzyme alone and in combination with the M182T mutation indicate that the M182T substitution acts at the level of folding but does not affect the thermodynamic stability of TEM-1 β-lactamase. Thus, the M182T substitution is an example of a naturally occurring mutation that has evolved to alter the folding pathway of a protein and confer a selective advantage during the evolution of drug resistance.
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影响因子：
15.9
作者：
Jacoby, George A.
通讯作者：
Jacoby, George A.
影响因子：
8
作者：
G. Georgiou;P. Valax;M. Ostermeier;P. Horowitz
通讯作者：
G. Georgiou;P. Valax;M. Ostermeier;P. Horowitz
影响因子：
--
作者：
Senear,DF;Bolen,DW
通讯作者：
Bolen,DW
TEM-72，一种在意大利奇异变形杆菌和摩根氏菌中检测到的新型广谱 β-内酰胺酶
影响因子：
4.9
作者：
M. Perilli;B. Segatore;Maria Rosaria De Massis;M. L. Riccio;C. Bianchi;A. Zollo;G. Rossolini;G. Amicosante
通讯作者：
G. Amicosante
影响因子：
2.1
作者：
ARLET, G;BRAMI, G;PHILIPPON, A
通讯作者：
PHILIPPON, A