Activation for catalysis of penicillin-binding protein 2a from methicillin-resistant Staphylococcus aureus by bacterial cell wall
Activation for catalysis of penicillin-binding protein 2a from methicillin-resistant Staphylococcus aureus by bacterial cell wall
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DOI：
10.1021/ja0434376
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发表时间：
2005-02-23
影响因子：
15
通讯作者：
Mobashery, S
中科院分区：
文献类型：
--
作者：
Fuda, C;Hesek, D;Mobashery, S
耐甲氧西林金黄色葡萄球菌 (MRSA) 获得了一种独特的青霉素结合蛋白 (PBP)，即 PBP 2a，该蛋白使该生物体对所有可用的 β-内酰胺抗生素的作用产生耐药性。 PBP 2a 的 X 射线结构显示其活性位点处于闭合构象，这与对 β-内酰胺抗生素的抑制作用具有抗性一致。然而，众所周知，PBP 2a 强烈地交联 S。金黄色葡萄球菌细胞壁，这是它的生理功能。本文显示，细菌细胞壁的合成片段以可饱和方式与PBP 2a结合，并引起蛋白质构象变化，使得活性位点更容易与β-内酰胺抗生素结合。这些观察和测量指出了一种新的自然策略，可以使 PBP 2a 的活性位点免受抗生素的抑制活性影响，但通过关键细胞壁交联反应所需的构象变化，它可以被聚合物细胞壁所利用。
Methicillin-resistantStaphylococcus aureus(MRSA) has acquired a unique penicillin-binding protein (PBP), PBP 2a, which has rendered the organism resistant to the action of all available β-lactam antibiotics. The X-ray structure of PBP 2a shows the active site in a closed conformation, consistent with resistance to inhibition by β-lactam antibiotics. However, it is known that PBP 2a avidly cross-links theS. aureuscell wall, which is its physiological function. It is shown herein that synthetic fragments of the bacterial cell wall bind in a saturable manner to PBP 2a and cause a conformational change in the protein that makes the active site more accessible to binding to a β-lactam antibiotic. These observations and measurements point to a novel strategy by nature to keep the active site of PBP 2a sheltered from the inhibitory activity of the antibiotics, yet it becomes available to the polymeric cell wall by a requisite conformational change for the critical cell wall cross-linking reaction.