Molecular dissection of a novel protein-protein interaction: structure and mechanism of the staphylococcal fusidic acid-resistance protein FusB

新型蛋白质-蛋白质相互作用的分子解析：葡萄球菌夫西地酸抗性蛋白FusB的结构和机制

• 批准号: BB/H018433/1
• 负责人: Alex O'Neill
• 金额: $ 40.44万
• 依托单位: University of Leeds
• 依托单位国家: 英国
• 项目类别: Research Grant
• 财政年份: 2010
• 资助国家: 英国
• 起止时间: 2010 至 无数据
• 项目状态: 已结题
• 来源: https://gtr.ukri.org/projects?ref=BB%2FH018433%2F1
• 关键词: Molecular; dissection; novel; protein; interaction

Resistance to antibiotics among bacteria is an ever-growing problem, since it interferes with our ability to successfully treat bacterial infections. In order to preserve the activity of existing antibiotics, and to guide the development of new antibiotics which are less resistance-prone, it will be essential to understand in detail the mechanisms by which bacteria develop such resistance. Fusidic acid is an important antibiotic for the treatment of bacterial infections caused by the 'superbug', Staphylococcus aureus. The drug works by interfering with the function of a protein known as elongation factor-G (EF-G) that helps the bacterium make proteins. However, an increasing number of strains of S. aureus are becoming resistant to this drug because they produce a protein called FusB that binds to EF-G and protects it from the antibiotic. Recent work in our laboratory suggests that this FusB resistance mechanism is highly unusual, and unlike most other antibiotic resistance mechanisms characterized to date. Furthermore, it appears that the FusB protein not only functions to protect the cell from fusidic acid, but also performs an accessory role in the cellular manufacture of proteins. Consequently, it is of significant fundamental scientific interest. The mechanism by which FusB performs its native role and causes resistance to fusidic acid remain poorly understood. To better understand how FusB achieves this, we aim to solve the 3-D structure of the FusB protein, alone and when bound to the EF-G protein, using a technique known as Nuclear Magnetic Resonance (NMR) spectroscopy. In conjunction with experiments to examine in detail how these proteins bind together, these studies will provide significant insights into FusB and the mechanism by which it carries out its biological role(s). This information may allow us to devise approaches for blocking the activity of FusB in bacterial cells, and overcoming resistance to fusidic acid in S. aureus.

细菌对抗生素的耐药性是一个日益严重的问题，因为它干扰了我们成功治疗细菌感染的能力。为了保持现有抗生素的活性，并指导开发不易产生耐药性的新抗生素，有必要详细了解细菌产生耐药性的机制。夫西地酸是一种重要的抗生素，用于治疗由“超级细菌”金黄色葡萄球菌引起的细菌感染。这种药物通过干扰一种被称为延伸因子-G（EF-G）的蛋白质的功能来发挥作用，这种蛋白质有助于细菌制造蛋白质。然而，越来越多的S.金黄色葡萄球菌对这种药物产生耐药性，因为它们产生一种称为FusB的蛋白质，这种蛋白质与EF-G结合并保护它免受抗生素的侵害。我们实验室最近的工作表明，这种FusB耐药机制是非常不寻常的，与迄今为止大多数其他抗生素耐药机制不同。此外，似乎FusB蛋白不仅起保护细胞免受夫西地酸的作用，而且在蛋白质的细胞制造中起辅助作用。因此，它具有重大的基本科学意义。FusB发挥其天然作用并引起夫西地酸耐药性的机制仍知之甚少。为了更好地理解FusB是如何实现这一点的，我们的目标是使用一种称为核磁共振（NMR）光谱的技术来解决FusB蛋白的3-D结构，单独和与EF-G蛋白结合时。结合详细研究这些蛋白质如何结合在一起的实验，这些研究将为FusB及其发挥生物学作用的机制提供重要的见解。这一信息可能使我们能够设计出阻断细菌细胞中FusB活性的方法，并克服S.金黄色。

项目成果

A target-protection mechanism of antibiotic resistance at atomic resolution: insights into FusB-type fusidic acid resistance.

• DOI: 10.1038/srep19524
• 发表时间: 2016-01-19
• 期刊: Scientific reports
• 影响因子: 4.6
• 作者: Tomlinson JH;Thompson GS;Kalverda AP;Zhuravleva A;O'Neill AJ
• 通讯作者: O'Neill AJ

Ribosome clearance by FusB-type proteins mediates resistance to the antibiotic fusidic acid

• DOI: 10.1073/pnas.1117275109
• 发表时间: 2012-02-07
• 期刊: PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
• 影响因子: 11.1
• 作者: Cox, Georgina;Thompson, Gary S.;O'Neill, Alexander J.
• 通讯作者: O'Neill, Alexander J.

Mutagenesis mapping of the protein-protein interaction underlying FusB-type fusidic acid resistance.

• DOI: 10.1128/aac.00198-13
• 发表时间: 2013-10
• 期刊: Antimicrobial agents and chemotherapy
• 影响因子: 4.9
• 作者: Cox G;Edwards TA;O'Neill AJ
• 通讯作者: O'Neill AJ