Elucidating allosteric signal disruption in PBP2a: impact of N146K/E150K mutations on ceftaroline resistance in methicillin-resistant Staphylococcus aureus

IF 3 3区 生物学 Q3 BIOCHEMISTRY & MOLECULAR BIOLOGY
Fangfang Jiao, Ran Xu, Qing Luo, Xinkang Li, Henry H. Y. Tong, Jingjing Guo
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引用次数: 0

Abstract

Ceftaroline (CFT) effectively combats methicillin-resistant Staphylococcus aureus (MRSA) by binding to the allosteric site on penicillin-binding protein 2a (PBP2a) and activating allosteric signals that remotely open the active pocket. However, the widespread clinical use of CFT has led to specific mutations, such as N146K/E150K, at the PBP2a allosteric site, which confers resistance to CFT in MRSA by disrupting the transmission of allosteric signals. Herein, computational simulations were employed to elucidate how the mutations disrupt the transmission of allosteric signals, thereby enhancing the resistance of MRSA to CFT. Specifically, the mutations alter the salt bridge network and electrostatic environment, resulting in a dynamic setting and decreased binding affinity of CFT within the allosteric pocket. Additionally, dynamical network analysis and the identification of allosteric pathways revealed that the reduced binding affinity diminishes the propagation of allosteric signals to the active site. Further evaluations demonstrated that this diminished signaling reduces the openness of the active pocket in the mutant systems, with “gatekeeper” residues and functional loops remaining partially closed. Redocking experiments confirmed that mutations lead to decreased docking scores and unfavorable docking poses for CFT within the active pocket. These findings highlight the complex interactions between structural changes induced by mutations and antibiotic resistance, providing crucial insights for developing new therapeutic strategies against MRSA resistance.

阐明PBP2a变构信号中断:N146K/E150K突变对耐甲氧西林金黄色葡萄球菌头孢他林耐药的影响
头孢他林(CFT)通过结合青霉素结合蛋白2a (PBP2a)上的变构位点并激活远程打开活性口袋的变构信号,有效对抗耐甲氧西林金黄色葡萄球菌(MRSA)。然而,CFT的广泛临床应用导致了PBP2a变构位点的特异性突变,如N146K/E150K,这使得MRSA通过破坏变构信号的传递而对CFT产生耐药性。本文采用计算模拟来阐明突变如何破坏变构信号的传递,从而增强MRSA对CFT的抗性。具体来说,突变改变了盐桥网络和静电环境,导致变构口袋内CFT的动态设置和结合亲和力降低。此外,动态网络分析和变构途径的鉴定表明,结合亲和力的降低减少了变构信号向活性位点的传播。进一步的评估表明,这种减少的信号减少了突变系统中活性口袋的开放性,“守门人”残基和功能环保持部分关闭。再对接实验证实,突变导致主动口袋内CFT的对接分数下降和对接姿势不利。这些发现突出了突变引起的结构变化与抗生素耐药性之间的复杂相互作用,为开发针对MRSA耐药性的新治疗策略提供了重要见解。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
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来源期刊
Journal of Computer-Aided Molecular Design
Journal of Computer-Aided Molecular Design 生物-计算机:跨学科应用
CiteScore
8.00
自引率
8.60%
发文量
56
审稿时长
3 months
期刊介绍: The Journal of Computer-Aided Molecular Design provides a form for disseminating information on both the theory and the application of computer-based methods in the analysis and design of molecules. The scope of the journal encompasses papers which report new and original research and applications in the following areas: - theoretical chemistry; - computational chemistry; - computer and molecular graphics; - molecular modeling; - protein engineering; - drug design; - expert systems; - general structure-property relationships; - molecular dynamics; - chemical database development and usage.
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