Centre in Artificial Intelligence Driven Drug Discovery, Faculty of Applied Sciences, Macao Polytechnic University, Macao, China.
College of Life Sciences, Nanjing Agricultural University, Nanjing, China.
Antimicrob Agents Chemother. 2023 Dec 14;67(12):e0089523. doi: 10.1128/aac.00895-23. Epub 2023 Nov 16.
Methicillin-resistant (MRSA) acquires high-level resistance against β-lactam antibiotics by expressing penicillin-binding protein 2a (PBP2a). PBP2a is a cell wall-synthesizing protein whose closed active site exhibits a reduced binding affinity toward β-lactam antibiotics. Ceftaroline (CFT), a fifth-generation cephalosporin, can effectively inhibit the PBP2a activity by binding to an allosteric site to trigger the active site opening, allowing a second CFT to access the active site. However, the essential mechanism behind the allosteric behavior of PBP2a remains unclear. Herein, computational simulations are employed to elucidate how CFT allosterically regulates the conformation and dynamics of the active site of PBP2a. While CFT stabilizes the allosteric domain surrounding it, it simultaneously enhances the dynamics of the catalytic domain. Specifically, the study successfully captured the opening process of the active pocket in the allosteric CFT-bound systems and discovered that CFT alters the potential signal-propagating pathways from the allosteric site to the active site. These findings reveal the implied mechanism of the CFT-mediated allostery in PBP2a and provide new insights into dual-site drug design or combination therapy against MRSA targeting PBP2a.
耐甲氧西林金黄色葡萄球菌（MRSA）通过表达青霉素结合蛋白 2a（PBP2a）获得对β-内酰胺类抗生素的高水平耐药性。PBP2a 是一种细胞壁合成蛋白，其封闭的活性位点对β-内酰胺类抗生素的结合亲和力降低。头孢他啶（CFT）是一种第五代头孢菌素，通过与变构位点结合可以有效抑制 PBP2a 的活性，从而触发活性位点的打开，使第二个 CFT 能够进入活性位点。然而，PBP2a 变构行为的基本机制尚不清楚。在此，通过计算模拟阐明了 CFT 如何变构调节 PBP2a 活性位点的构象和动力学。虽然 CFT 稳定了它周围的变构域，但同时也增强了催化域的动力学。具体来说，该研究成功地捕捉到了变构 CFT 结合系统中活性口袋的打开过程，并发现 CFT 改变了从变构位点到活性位点的潜在信号传递途径。这些发现揭示了 CFT 介导的 PBP2a 变构的隐含机制，并为针对靶向 PBP2a 的 MRSA 的双位点药物设计或联合治疗提供了新的见解。
