Disruption of allosteric response as an unprecedented mechanism of resistance to antibiotics.
Disruption of allosteric response as an unprecedented mechanism of resistance to antibiotics.
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变构反应的破坏是对抗生素抗药性的前所未有的机制。
DOI：
10.1021/ja5030657
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发表时间：
2014-07-16
影响因子：
15
通讯作者：
Mobashery, Shahriar
中科院分区：
文献类型：
--
作者：
Fishovitz, Jennifer;Rojas-Altuve, Alzoray;Otero, Lisandro H.;Dawley, Matthew;Carrasco-Lopez, Cesar;Chang, Mayland;Hermoso, Juan A.;Mobashery, Shahriar
头孢洛林是最近批准用于治疗耐甲氧西林金黄色葡萄球菌（MRSA）感染的β-内酰胺抗生素，能够通过触发导致活性位点开放的变构构象变化来抑制青霉素结合蛋白2a（PBP 2a）。打开的活性位点现在容易受到第二分子头孢洛林的抑制，这是一种损害细胞壁生物合成并导致细菌死亡的事件。变构效应的触发通过第一抗生素分子在变构位点的核心内结合远离PBP 2a的活性位点60 nm而发生。我们的文件，通过动力学研究，并通过确定三个X-射线结构的突变体的PBP 2a，导致耐头孢洛林，这些临床突变体的影响是在MRSA的这种重要的蛋白质的变构触发中断。这是一种前所未有的抗生素耐药性机制。
Ceftaroline, a recently approved β-lactam antibiotic for treatment of infections by methicillin-resistant Staphylococcus aureus (MRSA), is able to inhibit penicillin-binding protein 2a (PBP2a) by triggering an allosteric conformational change that leads to the opening of the active site. The opened active site is now vulnerable to inhibition by a second molecule of ceftaroline, an event that impairs cell-wall biosynthesis and leads to bacterial death. The triggering of the allosteric effect takes place by binding of the first antibiotic molecule 60 Å away from the active site of PBP2a within the core of the allosteric site. We document, by kinetic studies and by determination of three X-ray structures of the mutant variants of PBP2a that result in resistance to ceftaroline, that the effect of these clinical mutants is the disruption of the allosteric trigger in this important protein in MRSA. This is an unprecedented mechanism for antibiotic resistance.
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影响因子：
4.8
作者：
Fuda, C;Suvorov, M;Mobashery, S
通讯作者：
Mobashery, S
影响因子：
4.8
作者：
Lovering, Andrew L.;Gretes, Michael C.;Strynadka, Natalie C. J.
通讯作者：
Strynadka, Natalie C. J.
DOI：
10.1038/nsb858
发表时间：
2002-11-01
期刊：
NATURE STRUCTURAL BIOLOGY
影响因子：
--
作者：
Lim, D;Strynadka, NCJ
通讯作者：
Strynadka, NCJ
影响因子：
2.6
作者：
Wu, SW;De Lencastre, H;Tomasz, A
通讯作者：
Tomasz, A
影响因子：
11.8
作者：
Farrell, David J.;Castanheira, Mariana;Jones, Ronald N.
通讯作者：
Jones, Ronald N.