Structural basis for the β-lactam resistance of PBP2a from methicillin-resistant Staphylococcus aureus
Structural basis for the β-lactam resistance of PBP2a from methicillin-resistant Staphylococcus aureus
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DOI：
10.1038/nsb858
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发表时间：
2002-11-01
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影响因子：
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通讯作者：
Strynadka, NCJ
中科院分区：
文献类型：
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作者：
Lim, D;Strynadka, NCJ
耐甲氧西林金黄色葡萄球菌(MRSA)的多重耐药性已成为世界范围内的主要临床问题。耐甲氧西林金黄色葡萄球菌对广谱β-内酰胺类抗生素耐药的关键决定因素是青霉素结合蛋白2a(PBP2a)。由于对β-内酰胺的亲和力较低，PBP2a提供转肽酶活性，以允许在β-内酰胺浓度下合成细胞壁，从而抑制通常由金黄色葡萄球菌产生的对β-内酰胺敏感的多氯联苯。一种可溶的PBP2a衍生物的晶体结构已被确定为1.8埃分辨率，并提供了高分子质量PBP的最高分辨率结构。此外，PBP2a与硝基呋喃、青霉素G和甲氧西林的酰基-PBP络合物的结构首次允许比较抗脂蛋白和酰化抗性的PBP。对这些形式的PBP2a活性部位的分析揭示了其耐药性的结构基础，并确定了新开发的β-内酰胺类药物中可能对高亲和力结合很重要的特征。
The multiple antibiotic resistance of methicillin-resistant strains of Staphylococcus aureus (MRSA) has become a major clinical problem worldwide. The key determinant of the broad-spectrum beta-lactam resistance in MRSA strains is the penicillin-binding protein 2a (PBP2a). Because of its low affinity for beta-lactams, PBP2a provides transpeptidase activity to allow cell wall synthesis at beta-lactam concentrations that inhibit the beta-lactam-sensitive PBPs normally produced by S. aureus. The crystal structure of a soluble derivative of PBP2a has been determined to 1.8 Angstrom resolution and provides the highest resolution structure for a high molecular mass PBP. Additionally, structures of the acyl-PBP complexes of PBP2a with nitrocefin, penicillin G and methicillin allow, for the first time, a comparison of an apo and acylated resistant PBP. An analysis of the PBP2a active site in these forms reveals the structural basis of its resistance and identifies features in newly developed beta-lactams that are likely important for high affinity binding.