摘要
能够抵抗多种抗生素作用的能力使耐甲氧西林金黄色葡萄球菌 (MRSA) 成为一种全球领先的人类病原体。在有机体中抵抗β-内酰胺抗生素的关键因素是盘尼西林结合蛋白 2a (PBP2a),一种在肽聚糖生物合成中催化两个相邻肽茎交联反应的酶。近期发表的PBPa2与头孢的复合体(一种显示抗MRSA作用的头孢菌素抗生素)的晶体结构显示了变构点位于距离转肽酶区域60-Å处。结合头孢至PBP2a的变构点引发了导致活性位点由一个关闭构象变为开放构象的构象变化。在此头孢的第二分子结合使酶抑制。MRSA中变构的发现是细胞壁生物合成调控的唯一已知实例,代表了对抗MRSA的一个新范例。本文总结了变构机制的目前知识、允许PBP2a催化的构象改变、以及一些临床菌株通过干扰变构机制来获得头孢耐药性的方法。
关键词: 变构机制,抗生素耐药性,β-内酰胺抗生素,构象变化,耐甲氧西林金黄色葡萄球菌,盘尼西林结合蛋白,X-射线晶体结构。
Current Medicinal Chemistry
Title:The Allosteric Site for the Nascent Cell Wall in Penicillin-Binding Protein 2a: An Achilles’ Heel of Methicillin-Resistant Staphylococcus aureus
Volume: 22 Issue: 14
Author(s): Ivan Acebron, Mayland Chang, Shahriar Mobashery and Juan A. Hermoso
Affiliation:
关键词: 变构机制,抗生素耐药性,β-内酰胺抗生素,构象变化,耐甲氧西林金黄色葡萄球菌,盘尼西林结合蛋白,X-射线晶体结构。
摘要: The ability to resist the effect of a wide range of antibiotics makes methicillin-resistant Staphylococcus aureus (MRSA) a leading global human pathogen. A key determinant of resistance to β-lactam antibiotics in this organism is penicillin-binding protein 2a (PBP2a), an enzyme that catalyzes the crosslinking reaction between two adjacent peptide stems during the peptidoglycan biosynthesis. The recently published crystal structure of the complex of PBP2a with ceftaroline, a cephalosporin antibiotic that shows efficacy against MRSA, has revealed the allosteric site at 60-Å distance from the transpeptidase domain. Binding of ceftaroline to the allosteric site of PBP2a triggers conformational changes that lead to the opening of the active site from a closed conformation, where a second molecule of ceftaroline binds to give inhibition of the enzyme. The discovery of allostery in MRSA remains the only known example of such regulation of cellwall biosynthesis and represents a new paradigm in fighting MRSA. This review summarizes the present knowledge of the allosteric mechanism, the conformational changes allowing PBP2a catalysis and the means by which some clinical strains have acquired resistance to ceftaroline by disrupting the allosteric mechanism.
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Ivan Acebron, Mayland Chang, Shahriar Mobashery and Juan A. Hermoso , The Allosteric Site for the Nascent Cell Wall in Penicillin-Binding Protein 2a: An Achilles’ Heel of Methicillin-Resistant Staphylococcus aureus, Current Medicinal Chemistry 2015; 22 (14) . https://dx.doi.org/10.2174/0929867322666150311150215
DOI https://dx.doi.org/10.2174/0929867322666150311150215 |
Print ISSN 0929-8673 |
Publisher Name Bentham Science Publisher |
Online ISSN 1875-533X |
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