Interrogating the nisin:lipid II interaction: a chemical biology approach

探究乳链菌肽:脂质 II 相互作用:化学生物学方法

基本信息

  • 批准号:
    EP/V033808/1
  • 负责人:
  • 金额:
    $ 96.74万
  • 依托单位:
  • 依托单位国家:
    英国
  • 项目类别:
    Research Grant
  • 财政年份:
    2022
  • 资助国家:
    英国
  • 起止时间:
    2022 至 无数据
  • 项目状态:
    未结题

项目摘要

Antibiotic resistant bacterial infections are becoming an increasing threat to global public health. A recently published UK Government document, the O'Neill report (2016) estimates that 10 million lives a year could be lost by 2050 if we do not tackle this issue. Part of the problem is that little investment in new antimicrobials has taken place in industry in decades, with the last new class of antibiotics discovered over 30 years ago. This has generated a renewed interest in natural products as a source of potent antimicrobial drugs. One class of natural products that are being intensively studied as possible leads are the lantibiotics. The best known of these, nisin, is produced by one strain of bacteria in order to kill off competing bacteria, and has been successfully used as a food preservative for many years. However, its complex structure, difficulties in synthesis, and poor biological properties mean that is has not yet been exploited as a possible antimicrobial drug to combat bacterial infections in humans. It is known that nisin targets a complex lipid, lipid II, which is only found in bacteria. As lipid II is critical for bacteria to be able to synthesise their cell wall, it is difficult for bacteria to evolve resistance to antimicrobial agents that target lipid II. Importantly, nisin and lipid II fit together to form an ordered pore structure that results in rupture of the bacterial membrane and the death of the bacterial cell. It is therefore very important that we understand how this pore forms and what the important interactions are between the nisin and lipid II components: however, current techniques for studying the structure of pores in membranes do not have high enough resolution to see the details of these interactions.The collaborating research groups have previously developed powerful methods for synthesising the challenging structures of nisin and lipid II, for analyzing how pore form in lipid membranes, and for screening new antibacterials against pathogens such as MRSA. In this proposal, we will systematically design and synthesise variants of nisin and lipid II, and for each structural variation we will then try to assemble the pore complex. The process will be akin to piecing together a 3-D jigsaw at the nanoscale, varying each of the pieces of the jigsaw one by one, to see which parts of the nisin and lipid II are crucial to successful assembly, and which parts are not involved in complex formation. This information will lead to a detailed model for the nisin:lipid II pore structure, and will eventually enable pharmaceutical companies to design simplified lantibiotics as leads for next generation antimicrobials.
抗生素耐药性细菌感染正日益成为全球公共卫生的威胁。最近发布的英国政府文件《奥尼尔报告》(2016 年)估计,如果我们不解决这个问题,到 2050 年,每年可能会有 1000 万人丧生。部分问题在于,几十年来,工业界对新型抗菌药物的投资很少,最后一类新型抗生素是在 30 多年前发现的。这引起了人们对作为有效抗菌药物来源的天然产物的新兴趣。正在深入研究作为可能的先导物质的一类天然产物是羊毛硫抗生素。其中最著名的是乳链菌肽,它是由一种细菌产生的,目的是杀死竞争细菌,多年来已成功用作食品防腐剂。然而,其复杂的结构、合成困难和较差的生物学特性意味着它尚未被开发为对抗人类细菌感染的可能的抗菌药物。众所周知,乳链菌肽针对的是一种复杂的脂质,即脂质 II,这种脂质仅存在于细菌中。由于脂质 II 对于细菌合成细胞壁至关重要,因此细菌很难对针对脂质 II 的抗菌药物产生耐药性。重要的是,乳链菌肽和脂质 II 结合在一起形成有序的孔结构,导致细菌膜破裂和细菌细胞死亡。因此,了解这种孔的形成方式以及乳链菌肽和脂质 II 成分之间的重要相互作用是非常重要的:然而,当前研究膜孔结构的技术没有足够高的分辨率来观察这些孔的细节。合作研究小组此前已开发出强大的方法来合成乳链菌肽和脂质 II 的挑战性结构,分析脂质膜中孔的形成方式,以及筛选针对 MRSA 等病原体的新型抗菌药物。在本提案中,我们将系统地设计和合成乳链菌肽和脂质 II 的变体,然后针对每种结构变体,我们将尝试组装孔复合物。该过程类似于将纳米级的 3D 拼图拼凑在一起,逐一改变拼图的每一块,以查看乳链菌肽和脂质 II 的哪些部分对于成功组装至关重要,哪些部分不是参与复杂的形成。这些信息将产生乳链菌肽:脂质 II 孔结构的详细模型,并最终使制药公司能够设计简化的羊毛硫抗生素作为下一代抗菌药物的先导物。

项目成果

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